Tricyclic compounds and drug compositions containing the same

ABSTRACT

Compounds having a β-3 adrenaline receptor agonist and are useful as drugs for the treatment and prevention of diabetes, obesity, hyperlipemia, etc., represented by a general formula (I) and salts thereof, and a process for producing these, and their intermediates, wherein R represents hydrogen or methyl; R 1  represents hydrogen, halogen, hydroxy, benzyloxy, amino, or hydroxymethyl; R 2  represents hydrogen, hydroxymethyl, NHR 3 , SO 2  NR 4  R 4&#39; , or nitro; R 6  represents hydrogen or lower alkyl; and X represents nitrogen, R 9  represents hydrogen, one of R 7  and R 8  represent hydrogen, and the other thereof represents hydrogen, amino, acetylamino, or hydroxy.

This application is a 371 of PCT/JP96/03689 filed Dec. 18, 1996.

FIELD OF THE INVENTION

The present invention relates to novel tricyclic compounds and to drugcompositions containing such tricyclic compounds.

BACKGROUND OF THE INVENTION

In the past, it was accepted that β-adrenaline receptors are classifiedinto two groups β1 and β2, wherein the stimulation by β1 induces anincrease in the cardiac rate and the stimulation by β2 brings aboutrelaxation in the smooth muscle tissue and lowering of blood pressure.Arch et al discovered a compound which exhibits scarce activities to β1and β2 but emphasizes lipolysis of fatty cells, wherefrom they have madeclear the existence of a third receptor [Nature, 309, 163-165 (1984)].Afterwards, the primary structure thereof was clarified [Emorine et al:Science, Vol. 245, 1118-1121 (1989)] and the receptor was named as β3.

Recently, it has been shown that compounds exhibiting a β3-activity areuseful as a drug for preventive treatment of diabetes, obesity,hyperlipemia, digestive diseases and depression [Int. J. Obesity 8(suppl. 1), 93-102 (1984); Nature, 309, 163-165(1984); U.S. Pat. No.5,120,766; Brit. J. Pharmacol.,103, 1351-1356 (1991); Eur. J.Pharmacol., 219, 193-201 (1992)].

Various compounds with correlation to β3 have been reported in theliteratures, for example, a compound (BRL 37344) having the followingmolecular structure ##STR1## as disclosed in EP 023 385 and in Drugs ofthe Future, Vol. 16, 797-800 (1991); a compound (CL316, 243) having thefollowing molecular structure ##STR2## as disclosed in EP 0 455 006 andJ. Med. Chem., Vol. 35, 3081-3084 (1992); a compound having thefollowing molecular structure ##STR3## as disclosed in W09429290; and acompound having the following molecular structure ##STR4## as disclosedin EP 0 659 737 in Example 1 thereof. All these compounds have molecularstructures different clearly from that of the compound according to thepresent invention.

There was known a compound exhibiting a function for increasing themyocardial contraction strength and for antagonizing obesity representedby the following structural formula ##STR5## as disclosed in EP 171 702,which is distinguished from the compound according to the presentinvention in that it has a strong pharmacological activity onto theheart and has a molecular structure quite different from that of thecompound according to the present invention.

Further, a compound exhibiting an α,β-blocking activity, namely, afunction of lowering the blood pressure, represented by the followingstructural formula ##STR6## is disclosed in Japanese Patent Kokais Sho55-53262 and Sho 58-41860 and a compound exhibiting a vasodilatoricfunction represented by the following structural formula ##STR7## isdisclosed in DE 2 651 572. They are different from the compoundaccording to the present invention in the molecular structure and infunction.

There is a demand for a novel and effective medicament or pharmaceuticcomposition which can be used for therapuetic treatment and preventivetreatment of diseases correlating to β3, such as diabetes, obesity andhyperlipemia.

DISCLOSURE OF THE INVENTION

The inventors in sound research for responding to the existing demand,by synthesizing various compounds and examining their functions reachedthe discovery that novel tricyclic compounds represented by the generalformula (I) given below had β3-activities with functions for loweringblood sugar value and for lipolysis, which has led to the completion ofthe present invention.

Thus, the present invention consists in a compound represented by thegeneral formula (I) or a salt thereof: ##STR8## in which R representshydrogen atom or methyl, R¹ stands for hydrogen atom, halogen atom,hydroxy, benzyloxy, amino or hydroxymethyl, R² stands for hydrogen atom,hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogenatom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ being a lower alkyl,benzyl or NR⁴ R^(4') and R^(6') being hydrogen atom or lower alkyl, andR⁴ and R^(4') may be identical with or different from each other andstand each for hydrogen atom, lower alkyl or benzyl, R⁶ representshydrogen atom or lower alkyl, X stands for a secondary nitrogen atom,oxygen atom, sulfur atom or methylene and, in case X is secondarynitrogen atom, oxygen atom or sulfur atom, R⁹ stands for hydrogen atomand either one of R⁷ and R⁸ is hydrogen atom and the other one ishydrogen atom, amino, acetylamino or hydroxy, or, in case X ismethylene, both R⁷ and R⁸ are hydrogen atom and R⁹ stands for hydrogenatom, amino, acetylamino or hydroxy, *1 indicates an asymmetric carbonatom and *2 indicates that the carbon atom is asymmetric provided thatR⁶ is lower alkyl.

According to the present invention, there may be exemplified for thehalogen atom fluorine atom, chlorine atom, bromine atom or iodine atom,among them, fluorine atom and chlorine atom are preferred. In thecontext of the present invention, "lower alkyl" means a straight orbranched chain saturated hydrocarbon having 1-4 carbon atoms, such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl andt-butyl.

In the formula (I), R may preferably be hydrogen atom, while R mayfavorably be also methyl for reason of providing more higherselectivity.

R¹ stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino orhydroxymethyl. A preferred example of the compound represented by thegeneral formula (I) is one in which R¹ denotes hydrogen atom. Alsopreferred example of the compound represented by the general formula (I)is one in which R¹ denotes amino or hydroxymethyl group. A furtherpreferred example of the compound represented by the general formula (I)is one in which R¹ denotes halogen atom or hydroxyl or benzyloxy group.

R² stands for hydrogen atom, hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') ornitro. A preferred example of the compound represented by the generalformula (I) is one in which R² is hydrogen atom. Also preferred exampleof the compound represented by the general formula (I) is one in whichR² is hydroxymethyl or nitro group. A further preferred example of thecompound represented by the general formula (I) is one in which R²stands for NHR³ or SO₂ NR⁴ R'. R³ in the group NHR³ may be hydrogenatom, methyl, SO₂ R⁵, formyl or CONHR^(6'), wherein preference is givenespecially to NHR³ which is NH₂, NHMe, NHSO₂ R⁵ and NHCONHR^(6'), amongwhich NHSO₂ R⁵ is more preferable. In the group NHSO₂ R⁵, R⁵ stands forlower alkyl, benzyl or NR⁴ R^(4'). R⁴ and R^(4') may either be identicalwith or different from each other and may stand each for hydrogen atom,lower alkyl or benzyl, wherein either one of R⁴ and R^(4') is preferablyhydrogen.

Concrete examples of NR⁴ R^(4') include amino, methylamino, ethylamino,propylamino, benzylamino, dimethylamino, diethylamino, dipropylamino,methylethylamino, methylpropylamino and methylbenzylamino, among whichpreference is given to methylamino and dimethylamino. Therefore,preferred concrete examples of NHSO₂ R⁵ include NHSO₂ Me, NHSO₂ Et,NHSO₂ CH₂ Ph, NHSO₂ NH₂, NHSO₂ NHMe, NHSO₂ NHEt, NHSO₂ NMe₂, NHSO₂ NEt₂,NHSO₂ NMeEt and NHSO₂ NMeCH₂ Ph. R^(6') in the group NHCONHR^(6') ishydrogen atom or lower alkyl. Concrete examples of NHCONHR^(6') includeNHCONH₂, NHCONHMe, NHCONHEt and NHCONHPr. Concerning the group SONR⁴R^(4') for the group R², the groups R⁴ and R^(4') have the same meaningsas given above and may either be identical with or different from eachother and may stand each for hydrogen atom, lower alkyl or benzyl,wherein it is preferable that either one of R⁴ and R^(4') is hydrogenatom. Therefore, concrete examples of the group SO₂ NR⁴ R^(4') includeSO₂ NH₂, SO₂ NHMe, SO₂ NHEt, SO₂ NMe₂, SO₂ NEt₂, SO₂ NHCH₂ Ph and SO₂NMeCH₂ Ph.

R⁶ represents hydrogen atom or lower alkyl. Preferred examples includehydrogen atom, methyl and ethyl. Here, preference is given to the casewhere it stands for hydrogen atom.

X stands for secondary nitrogen atom, oxygen atom, sulfur atom ormethylene. A preferred example of the compound is one in which X issecondary nitrogen atom, namely, the tricyclic skeleton is constitutedof carbazole group. Here, the groups R⁷, R⁸ and R⁹ have the meanings asgiven previously.

The symbol *1 in the general formula (I) indicates an asymmetric carbonatom and, in case R⁶ is lower alkyl, the symbol *2 also indicates anasymmetric carbon atom. In this case, the compound of the generalformula (I) may be present in four isomers,namely, (R,R), (R,S), (S,S)and (S,R) represented by the sequence of (*1, *2). In case R⁶ ishydrogen atom, two isomers are possible. The present inventionencompasses not only each optically pure isomer, but also mixtures oftwo voluntarily selected isomer, of three voluntarily selected isomersand of all four isomers. From the point of view of development of thepharmacological activity, an asymmetric carbon atom (*1) in theethanolamino chain may preferably have an absolute configuration (R).Concerning the asymmetric carbon atom (*1) forN-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,especially preferred examples are R-hydroxy compounds.

For the compound according to the present invention, there are veryfavorable groups of combinations of the substituent groups. In thefollowing, the symbols R⁶, X, R⁷, R⁸, R⁹, *1 and *2 for the generalformula (I) have the meanings as defined above, so long as no specialmention is made.

When R² in the general formula (I) for the compound according to thepresent invention represents hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') ornitro, it is preferable that the group R¹ is in the 4- or 5-position,wherein preference is given to the case where R¹ is in 4-position. WhenR² is hydrogen atom, it is more preferable that R¹ is in the 2-position.

Preferred examples of the compound represented by the general formula(I) or the salt thereof according to the present invention are those inwhich the combination of the substituent groups in the general formula(I) is such that "R represents hydrogen atom, R¹ stands for hydrogenatom, a halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl and R²stands for hydrogen atom, hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro,wherein R³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6'), withR⁵ being lower alkyl, benzyl or NR⁴ R^(4') and R⁴ and R^(4') may beidentical with or different from each other and stand each for hydrogenatom, lower alkyl or benzyl and R^(6') has the meaning as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents hydrogen atom, R¹ stands forhydrogen atom, fluorine atom, chlorine atom, hydroxy or benzyloxy and R²stands for hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ ishydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6') and either one of R⁴and R^(4') is hydrogen atom and the other one is hydrogen atom, loweralkyl or benzyl, with R⁵ being lower alkyl, benzyl or dimethylamino andR^(6') being the same as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents hydrogen atom, R¹ stands forhydrogen atom, halogen atom, hydroxy or benzyloxy and R² stands forhydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogenatom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ being lower alkyl,benzyl or NR⁴ R^(4') and R⁴ and R^(4') may be identical with ordifferent from each other and stand each for hydrogen atom, a loweralkyl or benzyl and R^(6') has the meaning as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents hydrogen atom, R¹ stands forhydrogen atom, fluorine atom, chlorine atom, hydroxy or benzyloxy and R²stands for hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ ishydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6') and either one of R⁴and R^(4') is hydrogen atom and the other one is hydrogen atom, loweralkyl, benzyl, with R⁵ being a lower alkyl, benzyl or dimethylamino andR^(6') being the same as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R and R¹ represent each hydrogen and R² standsfor hydroxymethyl, NHR³ or SO₂ NR⁴ R^(4'), wherein R³ is hydrogen atom,methyl, SO₂ R⁵, formyl or CONHR^(6') with R⁵ being lower alkyl, benzylor NR⁴ R^(4') and R⁴ and R^(4') may be identical with or different fromeach other and stand each for hydrogen atom, lower alkyl or benzyl, andR^(6') being the same as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R and R¹ represent each hydrogen atom and R²stands for hydroxymethyl, NHR³ or SO₂ NR⁴ R^(4'), wherein R³ is hydrogenatom, methyl, SO₂ R⁵, formyl or CONHR^(6') and either one of R⁴ andR^(4') is hydrogen atom and the other one is hydrogen atom, lower alkylor benzyl, with R⁵ being lower alkyl, benzyl or dimethylamino and R⁶being the same as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents hydrogen atom, R¹ stands forhalogen atom or hydroxy and R² stands for NHSO₂ R⁵ or SO₂ NR⁴ R^(4'),wherein R⁵ is lower alkyl, benzyl or NR⁴ R^(4') and R⁴ and R^(4') may beidentical with or different from each other and stand each for hydrogenatom, lower alkyl or benzyl".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents hydrogen atom, R¹ stands forfluorine atom, chlorine atom or hydroxy and R² stands for NHSO₂ R⁵ orSO₂ NR⁴ R^(4'), wherein either one of R⁴ and R^(4') is hydrogen atom andthe other one is hydrogen atom, lower alkyl or benzyl and R⁵ is loweralkyl, benzyl or dimethylamino".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R and R² represent each hydrogen atom and R¹stands for hydrogen atom, halogen atom or hydroxy".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R and R² represent each hydrogen atom and R¹stands for hydrogen atom, fluorine atom, chlorine atom or hydroxy".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents hydrogen atom, R¹ stands forhydrogen atom, halogen atom, hydroxy, amino or hydroxymethyl and R²stands for NHR³ or SO₂ NR⁴ R^(4'), wherein R³ is SO₂ R⁵, with R⁵ beinglower alkyl, benzyl or NR⁴ R^(4'), and R⁴ and R^(4') may be identicalwith or different from each other and stand each for hydrogen atom,lower alkyl or benzyl".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl and R²stands for hydrogen atom, hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro,wherein R³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6'), withR⁵ being lower alkyl, benzyl or NR⁴ R^(4'), and R⁴ and R^(4') may beidentical with or different from each other and stand each for hydrogenatom, lower alkyl or benzyl and R^(6') has the meaning as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom, fluorine atom, chlorine atom, hydroxy or benzyloxy and R² standsfor hydrogen atom, hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, whereinR³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ beinglower alkyl, benzyl or NR⁴ R^(4'), and either one of R⁴ and R^(4') ishydrogen atom and the other one is hydrogen atom, lower alkyl or benzyland R^(6') has the meaning as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom, halogen atom, hydroxy or benzyloxy and R² stands forhydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogenatom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R³ being lower alkyl,benzyl or NR⁴ R^(4'), and R⁴ and R^(4') may be identical with ordifferent from each other and stand each for hydrogen atom, lower alkylor benzyl and R^(6') has the meaning as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom, fluorine atom, choline atom, hydroxy or benzyloxy and R² standsfor hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogenatom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ being lower alkyl,benzyl or dimethylamino, and either one of R⁴ and R^(4') is hydrogenatom and the other one is hydrogen atom, lower alkyl or benzyl andR^(6') has the meaning as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom and R² stands for hydroxymethyl, NHR³, SO₂ NR⁴ R^(4'), wherein R³is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ beinglower alkyl, benzyl or NR⁴ R^(4'), and R⁴ and R^(4') may be identicalwith or different from each other and stand each for hydrogen atom,lower alkyl or benzyl and R^(6') has the meaning as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom and R² stands for hydroxymethyl, NHR³ or SO₂ NR⁴ R^(4'), wherein R³is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ beinglower alkyl, benzyl or dimethylamino, and either one of R⁴ and R^(4') ishydrogen atom and the other one is hydrogen atom, lower alkyl or benzyland R^(6') has the meaning as given above".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for halogenatom or hydroxy and R² stands for NHSO₂ R⁵ or SO₂ NR⁴ R^(4'), wherein R⁵is lower alkyl, benzyl or NR⁴ R^(4'), and R⁴ and R^(4') may be identicalwith or different from each other and stand each for hydrogen atom,lower alkyl or benzyl".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for fluorineatom, chlorine atom or hydroxy and R² stands for NHSO₂ R⁵ or SO₂ NR⁴R^(4'), wherein either one of R⁴ and R^(4') is hydrogen atom and theother one is hydrogen atom, lower alkyl or benzyl and R⁵ is lower alkyl,benzyl or dimethylamino".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom, a halogen atom or hydroxy and R² stands for hydrogen atom".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom, fluorine atom, chlorine atom or hydroxy and R² stands for hydrogenatom".

Also preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that "R represents methyl, R¹ stands for hydrogenatom, halogen atom, hydroxy, amino or hydroxymethyl and R² stands forNHR³ or SO₂ NR⁴ R^(4'), wherein R³ is SO₂ R⁵, with R⁵ being lower alkyl,benzyl or NR⁴ R^(4'), and R⁴ and R^(4') may be identical with ordifferent from each other and stand each for hydrogen atom, lower alkylor benzyl".

Concrete examples of the compound represented by the general formula (I)according to the present invention include

(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(3-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(3-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(6-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(6-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

(R)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

(S)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

N-methyl-3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]benzenesulfonamide,

N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide,

(R)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

(S)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

N-[3-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

N-[5-[2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[3-[2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-phenyl]methanesulfonamide,

N-[3-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]formamide,

N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]formamide

N-[3-[2-[[1-(9H-carbazol-2-yloxy)propan-2R-yl]amino]-1-hydroxyethyl]phenyl]methanesulfonamide,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxy-3-nitrophenyl)ethanol,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-amino-4-hydroxyphenyl)ethanol,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]urea,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]urea,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]formamide,

N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N,N-dimethylsulfamide,

N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-(benzyloxy)phenyl]ethanol,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-hydroxyphenyl]ethanol,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-2-propanesulfonamide,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-nitrophenyl)ethanol,

N'-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]-N,N-dimethylsulfamide,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-aminophenyl)ethanol,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(hydroxymethyl)-4-hydroxyphenyl]ethanol,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-3-hydroxyphenyl]methanesulfonamide,

N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamide,

(R)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

(S)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

N-[3-[2-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

N-[5-[2-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-iodophenyl]methanesulfonamide,

N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]-N,N-dimethylsulfamide,

N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]-N,N-dimethylsulfamide,

(R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide,

(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenyl]methanesulfonamide,

(R)-N-[3-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

(R)-N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

(S)-N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N'-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

N-[3-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

(R)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

N-[5-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N'-[5-[2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]-N-benzyl-N-methylsulfamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxymethylphenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide,

N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N-benzyl-N-methylsulfamide,

N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-diethylsulfamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-aminophenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamideand

N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamide.

The followings are concrete examples of the compound in which both R¹and R².

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxyphenyl)ethanol,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-fluorophenyl)ethanol,

2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-hydroxyphenyl)ethanol,

(R,R)-2-[N-[1-(9H-carbazol-2-yloxy)propan-2-yl]amino]-1-phenyl]ethanol,

[2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

(R)-[2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

(S)-[2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[2-[N-[2-(3-acetylamino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[2-[N-[2-(3-amino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[2-[N-[2-(3-hydroxy-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol

[2-[N-[2-(6-amino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[2-[N-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[2-[N-[1-(9H-carbazol-2-yloxy)propan-2-yl]amino]-1-phenyl]ethanol and

[2-[N-[2-(dibenzofuran-3-yloxy)ethyl]amino]-1-phenyl]ethanol.

Examples of the compounds in which R stands for methyl include thefollowings.

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamide,

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-aminophenyl]methanesulfonamideand

N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-chlorophenyl]methanesulfonamide.

The compound represented by the general formula (I) can be produced, forexample, by the following method.

Production Process A

A compound represented by the general formula (II) ##STR9## [in whichR^(1') represents hydrogen atom, halogen atom, a protected hydroxylgroup protected by a protecting group A, a protected amino groupprotected by acetyl group or a protected hydroxymethyl group protectedby acetyl group, R^(2') stands for hydrogen atom, for a protectedhydroxymethyl group in which the hydroxyl group is protected by aprotecting group A"', for NHR^(3'), for SO₂ NR⁴ R^(4') or for nitro,wherein R^(3') represents a protecting group for the amino group,methyl,SO₂ R⁵, formyl or CONHR^(6'), with R⁵ being lower alkyl benzyl or NR⁴R^(4') and R^(6') being hydrogen atom or lower alkyl R⁴ and R^(4') maybe identical with or different from each other and stand each forhydrogen atom, lower alky or benzyl, R⁶ denotes hydrogen atom or loweralkyl, A' represents a protecting group for the hydroxyl group, B isbromine atom or iodine atom and *1 indicates an asymmetric carbon atom]is reacted with a compound represented by the general formula (III)##STR10## [wherein Y represents hydrogen atom, R⁶ is hydrogen atom orlower alkyl, X is secondary nitrogen atom, oxygen atom, sulfur atom ormethylene and, in case X is secondary nitrogen atom, oxygen atom orsulfur atom, R^(9') is hydrogen atom and either one of R^(7') and R^(8')is hydrogen atom and the other one is hydrogen atom, acetylamino or aprotected hydroxyl group protected by a protecting group A", or, in casethat X is methylene, both R^(7') and R^(8') are hydrogen atom and R^(9')stands for hydrogen atom, acetylamino or a protected hydroxyl groupprotected by a protecting group A", and *2 indicates asymmetric carbonatom, when R⁶ is lower alkyl], and the protecting groups A (proviso thatin case that R¹ is benzyloxy and the protecting group A is benzyl, theprotecting group A is not deprotected), A', A", A"' and the protectinggroup for amino group in R^(3') (proviso that if is exists), or theprotecting acetyl group in R^(1') are deprotected to obtain the compoundrepresented by the general formula (I), [wherein R represents hydrogenatom, R¹ stands for hydrogen atom, halogen atom, hydroxy, benzyloxy,amino or hydroxymethyl, R² stands for hydrogen atom, hydroxymethyl,NHR³, SO₂ NR⁴ R^(4') or nitro, proviso that R³ is hydrogen atom, methyl,SO₂ R⁵, formyl or CONHR^(6'), and R⁵ is lower alkyl, benzyl or NR⁴R^(4') and R⁴ and R^(4') may be identical with or different from eachother and are hydrogen atom, lower alkyl or benzyl group. R^(6') isrepresents hydrogen atom or lower alkyl.

As the protecting groups for protecting the hydroxyl groups, there is nospecial limitation so long as ordinary use is permitted and there mayusually be used as a protecting group which can be deprotected easilyand selectively, for example, benzyl or t-butyl-dimethylsilyl for theprotecting group A, triethylsilyl for the protecting groups A' and A"'and methyl or benzyl for the protecting group A". For introducing aprotecting group into the compound to be protected, known practice isemployed and, for example, a method is used for protecting the compoundby introducing therein benzyl group, in which the compound is reactedwith 1.1 molar times benzyl bromide at room temperature in a reactionsolvent, such as dimethylformamide, in the presence of potassiumcarbonate. For protecting the compound by introducing thereintriethylsilyl group, the compound is reacted with 1.2-2 molar timessilylating agent, such as triethylsilyl chloride, at a temperature inthe range of 0 to 30° C. in a reaction solvent, such as pyridine, for1-3 hours.

As the protecting group for protecting the amino group in thesubstituent R^(3'), there is no special limitation so long as ordinaryuse as a protecting group for protecting aniline is permitted and acetylgroup may usually be preferred therefor. For practising the acetylation,a reaction with acetic anhydride in a reaction solvent, such aspyridine, may be exemplified.

The coupling reaction of the compound represented by the general formula(II) with the amine represented by the general formula (III) may berealized using 1 to 1,5 moles of the amine of the general formula (III)per 1 mole of the halide of the general formula (II) in a polar solvent,such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, inthe presence of a proton capturing agent, for example, an amine, such astriethylamine or diisopropylethylamine, at a temperature in the rangefrom room temperature to 90° C., preferably by heating at 60° C., for5-10 hours.

Deprotection of the resulting product may be effected either insuccession or simultaneously, while deprotection in a successive orderof A", A', A"', the protecting agent for the amino group in R^(3') andat last A may be preferred. The deprotection of benzyl group for A andA" is realized by hydrogenolysis in a solvent, such as methanol, using acatalyst, such as palladium or nickel. In the case where the substituentR¹ in the general formula (I) is benzyloxy, there is no need ofelimination of benzyl group as the protecting group A. The deprotectionof benzyl or methyl as the protecting groups A and A" may be realized bytreating the product with a Lewis acid, such as boron tribromide, in asolvent, such as methylene chloride. The deprotection ofacetyl-protected hydroxyl group in the substituent R^(1') may berealized by a known procedure of hydrolysis of ester. Concretely, it maybe performed in an alcohol using an alkali at room temperature or byheating under reflux of the solvent. The deprotection of triethylsilylas the protecting group A' or A"' may be realized by treating theproduct by adding thereto acetic acid and 3-5 molar timestetrabutylammonium fluoride in a solvent of tetrahydrofuran at roomtemperature for 30-5 hours. The deprotection of the protecting group,such as acetyl, for the amino group in R^(3') or of the acetyl-protectedamino group in R^(1') may be realized either by treating the productwith hydrochloric acid at room temperature or by heating in a solvent,such as water or methanol, with an alkali.

The compound represented by the general formula(II) can be obtained bysubjecting a compound represented by the following general formula (V),##STR11## in which R^(1') and R^(2') have the same meanings as givenpreviously, to a reduction in the manner as described below, andreplacing the bromide, if the contemplated substituent group B in thegeneral formula (II) is iodine, iodide, followed by protection of thehydroxyl group.

The reduction of the compound represented by the general formula (V) maybe attained by using a reducing agent, such as a borane, when the stericconfiguration (*1) of the hydroxyl group of the compound represented bythe general formula (II) is racemic.

In case where either R- or S-optical isomer is to be obtained as to the*1 structure in the general formula (II), the reduction can be attainedby having resort to employment of a chiral assistant, such as given bythe following general formula (VI). ##STR12##

Thus, the reduction of the compound represented by the general formula(V) is effected using a borane in the presence of the above-mentionedchiral assistant. The reduction may preferably be performed in asolvent, such as tetrahydrofuran. The preparation of such a chiralassistant and the reaction therewith may be carried out in accordancewith the teachings in the literature [E. J. Corey et al, J. Org. Chem.,Vol.56, 442, (1991)].

After the reduction of the compound represented by the general formula(V), the bromide thereof is, if necessary, replaced with iodide by, forexample, treating the reduced compound with 3-10 times molar amount ofan iodizing agent, such as sodium iodide, in a solvent, such as acetone,with heating under reflux for 1-3 hours.

The hydroxyl group of the so-treated product is then protected by themethod described previously with a protecting group, such astriethylsilyl, to obtain the compound represented by the formula (II).

The compound represented by the general formula (V) is known and can besynthesized by methods given in literatures, for example, A. A. Larsenet al, J. Med. Chem., 10, 462 (1967); or C. Kaiser et al, J. Med. Chem.17, 49 (1974).

The compound represented by the general formula (III) can be obtained byreacting a compound represented by the general formula (VII) ##STR13##in which Y denotes a protecting group for the amino group, R⁶ and *2have the same meanings as those given previously, with a compoundrepresented by the general formula (VIII) ##STR14## in which X, R^(7'),R^(8') and R^(9') have the same meanings as those given previously. Asthe protecting group Y for protecting the amino group, there is nospecial limitation so long as a usual use is permitted and there may beexemplified one which can usually be deprotected easily, for example,benzyloxycarbonyl, a substituted benzyloxycarbonyl, t-butoxycarbonyl,acetyl or trifluoroacetyl.

The reaction of the compound represented by the general formula (VII)with the compound represented by the general formula (VIII) can berealized, for example, in an organic solvent usually in the presence ofa base at a temperature from room temperature to the reflux temperatureof the solvent employed. As the solvent, there may be employed, forexample, dimethylformamide, dimethylacetamide, acetonitrile, diglym andtetrahydrofuran. As the base, there may be employed, for example,potassium carbonate, sodium carbonate, sodium hydroxide, potassiumhydroxide, triethylamine, pyridine, sodium hydride or sodium methoxide,in an amount of, preferably, 1-10 moles per one mole of the compound ofthe general formula (VIII).

The compound represented by the general formula (III) can, inparticular, if the above reaction does not proceed promptly, also besynthesized in accordance with the process described in Bull. Chem. Soc.Japan, 55, 2504 (1982) or by an improvement thereof. For example, onemole of the alcohol compound is reacted with 2-5 moles of the compoundrepresented by the general formula (VII) in a solvent, such asdimethylformamide or acetonitrile, in the presence of 5-10 moles of 40%potassium fluoride-alumina at a temperature in the range from roomtemperature to 90° C. In the improved process, the above reaction isrealized with addition of 0.1-0.5 equivalent of potassium iodide.

Then, the protecting group Y for protecting the amino group isdeprotected to obtain the amine compound represented by the generalformula (III) wherein Y stands for hydrogen atom. The deprotection maybe effected by a usual method, for example, by a hydrogenolysis in asolvent, such as methanol, using a catalyst, such as palladium/carbonblack or by treating with hydrogen bromide/acetic acid. If theprotecting group Y is acetyl or trifluoroacetyl, the deprotection may beattained by treating with an alkali in a solvent, such as methanol, toobtain the compound represented by the general formula (III) in which Ydenotes hydrogen atom.

The compound represented by the general formula (VII) can be synthesizedfrom a commercial product of an amino alcohol having the substituent R⁶and a stereo structure of *2 by first protecting the amino group thereofwith a protecting group Y and, then, the resulting product is subjectedto bromination by a usual method. If there is an easily availableaminobromo compound, the contemplated compound can be obtained by merelyprotecting the amino group by a protecting group Y. For example, ahydrobromide salt of a commercial 2-bromoethylamine may be reacted withbenzyloxycarbonyl chloride in a solvent, such as methylene chloride, inthe presence of triethylamine under cooling with ice water.

The compound represented by the general formula (VIII) in which X standsfor secondary nitrogen atom, oxygen atom or sulfur atom and that inwhich X stands for methylene can be produced by the methods given below,respectively.

The compound of the general formula (VIII) in which X is secondarynitrogen atom, oxygen atom or sulfur atom, both R^(8') and R^(9') arehydrogen atom and R^(7') is hydrogen atom, acetylamino or a protectedhydroxyl group protected by a protecting group A" can be produced in amanner as follows:

Thus, starting from a commercial product of 2-hydroxycarbazole and3-methoxydibenzofuran or 3-hydroxydibenzothiophene which can besynthesized by method given in literature [H. Kudo et al, J. Heterocycl.Chem., 22(1), 215-218 (1985)],the compound represented by the formula(VIII) is obtained. The compound of the general formula (VIII) in whichR^(7') is a substituent group other than hydrogen atom can be obtainedby, for example, in such a manner that the hydroxyl group of acommercial product of 2-hydroxycarbazole is protected by benzylating it,then, nitration is effected to introduce nitro group at the position ofthe substituent group R^(7') and this is reduced into amino group,whereupon this amino group is acetylated or is subjected todiazotization with subsequent conversion into hydroxyl group, followedby protection of the resulting hydroxyl group by a protecting group A"and subsequent deprotection of the benzyl group to build up the compoundof the general formula (VIII).

For the nitration, ordinary methods given in the literatures may beemployed, wherein, for example, the benzyl-protected product issubjected to nitrationin acetic acid using an equivalent amount ofdiluted fuming nitric acid at a temperature of from room temperature to60° C. Reduction of the resulting nitro group may be effected by ausually employed method, for example, by hydrogenation in a solvent,such as methanol, in the presence of a catalyst, such as palladium oxideat room temperature or by using hydrochloric acid with iron powder or inthe presence of divalent tin at a temperature in the range from roomtemperature to the reflux temperature. The resulting amine may beacetylated using acetylchloride in a solvent, such as methylenechloride, at a temperature of from 0° C. to room temperature or may beconverted into hydroxyl group by first diazotizing it using, forexample, sodium nitrite, and, then, subjecting the resulting diazoniumsalt to a thermal decomposition in an acidic aqueous solution, followedby protection of the resulting hydroxyl group with a protecting group A"by the technique for protecting hydroxyl group described previously and,finally, deprotecting the benzyl group.

The compound of the general formula (VIII) in which X is secondarynitrogen atom, oxygen atom or sulfur atom, both R^(7') and R^(9') arehydrogen atom and R^(8') is hydrogen atom, acetylamino or a protectedhydroxyl group protected by a protecting group A" can be produced in themanner as follows:

Thus, it can be synthesized starting from a known compound, i.e.2-acetylcarbazole represented by the general formula (IX) ##STR15## inwhich X is secondary nitrogen atom, oxygen atom or sulfur atom (J. B.Kyziol et al, Tetrahedron, 36, 3017-3019 (1980)], 3-acetyldibenzofuran[M. I. Shevchuk etal, Zh. Obshch. Khim., 40 (8), 1717-1725 (1970)] or3-acetyldibenzothiophene [Phosphorus, Sulfur Silicon Relat. Elem.,72(1-4), 13-31 (1992), E. Camagine etal, J. Heterocycl. Chem., 6 (4),517-522 (1969)]. For the compound in which R^(8') is a substituent groupother than hydrogen atom, it may be processed, for example, by nitrating2-acetylcarbazole at its position of the substituent group R^(8'),followed by reduction of the resulting nitro group into amino group,whereupon the amino group is subjected to either acetylation ordiazotization with subsequent conversion into hydroxyl group, which isthen protected by a protecting group A" for protecting hydroxyl group.

For example, for producing the compound represented by the generalformula (VIII) from the so-obtained acethyl group-containing compound,namely, for converting the acetyl group into hydroxyl group, the acetylgroup at the 2-position of carbazole is oxidized by a peracid intoacetyloxy which is, then, subjected to hydrolysis. Other process stepsthan the oxidation of the acetyl group and the hydrolysis may beaccomplished in the same manner as in the case of introduction of R^(7')described above. The oxidation by a peracid can be realized using, forexample, m-chloro-perbenzoic acid and disodium hydrogenphosphate in asolvent, such as methylene chloride, at room temperature and thehydrolysis can be realized by, for example, using sodium hydroxide in amixed solvent of water/ethanol.

The compound represented by the general formula (VIII) in which X ismethylene (fluorene), both R^(7') and R^(8') are hydrogen atom andR^(9') is hydrogen atom or acetylamino is known and a commercial productthereof is available from, for example, the firm Sailor. In the casewhere R^(9') is a protected hydroxyl group protected by a protectinggroup A", the compound can be produced by protecting the hydroxyl groupof fluorene with benzyl group, de-protecting the acetyl group in theacetylamino group, diazotizing the resulting amino group, converting itinto hydroxyl group via a diazonium salt, protecting the resultinghydroxyl group by a protecting group A" for protecting hydroxyl groupand finally de-protecting the benzyl group. These reaction series can beperformed by the method described previously.

Alternatively, for producing the compound of the general formula (III)in which either one of R^(7'), R^(8') and R^(9') is a protected hydroxylup protected by a protecting group A", methods as given below may beincorporated.

Thus, the compound represented by the general formula (III) in which Ydenotes a protecting group for protecting amino group, R^(7'), R^(8')and R^(9') denote each acetyl group in accordance with X and R^(6') and*2 have the same meanings as those given previously is subjected tohydrolysis of the acetylamino group thereof into amino group. Theresulting amino group is diazotized and converted into hydroxyl group,which is then protected by a protecting group A", whereupon theprotecting group Y of the amino group is deprotected to obtain thecompound represented by the general formula (III) in which Y is hydrogenatom.

As a further alternative method, the compound represented by the generalformula (I) in which R is hydrogen atom can be obtained using a compoundrepresented by the general formula (IV) ##STR16## in which Y' ishydrogen atom or a protecting group for amino group and R^(1'), A', R⁶,X, R^(7'), R^(8'), R^(9'), *1 and *2 have the same meanings as thosegiven previously, as an important synthesis intermediate.

For producing the compound represented by the general formula (IV), thecompound represented by the general formula (II) in which R^(2') isnitro and the compound represented by the general formula (III) in whichY stands for hydrogen atom are brought into coupling reaction and, ifnecessary, the amino group of the reaction product is protected. Theprotecting group for the amino group in the substituent group Y' of thegeneral formula (IV) may be the same as that for the amino group in thesubstituent group Y explained above and the introduction and eliminationthereof may also be effected in the same manner.

For producing the compound represented by the general formula (I) usingthe compound represented by the general formula (IV) as a synthesisintermediate, the following techniques may be exemplified:

Thus, the compound represented by the general formula (IV) is firstreduced, namely, the nitro group thereof is reduced, to obtain acompound represented by the general formula (X) ##STR17## in which Y' isa protecting group for the amino group and R^(1'), A', R⁶, X, R^(7'),R^(8'), R^(9'), *1 and *2 have the same meanings as those givenpreviously.

For the above-mentioned reduction, the amino group of the compound ofthe general formula (IV) may preferably have been protected by theprotecting group Y' and the reduction may be performed by, for example,hydrogenating the compound in a solvent, such as methanol, in thepresence of a catalyst, such as palladium oxide, or by using a systememploying hydrochloric acid with iron powder or a divalent tin.

Thereafter, the resulting product is subjected to formylation,sulfonation or urearization of amine (aniline) in accordance with therequirement for providing various substituent groups for R³ by, forexample, a method described in the literature, C. Kaiser et al. J. Med.Chem., 17, 49 (1974), to convert it into a compound represented by thegeneral formula (XI) ##STR18## in which Y', R^(1'), A', R³, R⁶, X,R^(7'), R^(8'), R^(9'), *1 and *2 have the same meanings as those givenpreviously, whereupon the existing protecting groups among A, A',A" andthat for the amino group in Y' are de-protected by the method fordeprotection described previously, to produce the compound representedby the general formula (I) in which R is hydrogen atom.

The formylation mentioned above may be effected by, for example, heatingthe resulting product of the general formula (X) in ethyl formate or byreacting it with a mixture of formic acid/acetic anhydride at atemperature of from cooling with ice water to room temperature. Theabove mentioned sulfonation may be effected by, for example, reactingthe resulting compound of the general formula (X) with a sulfonylchloride substituted by a group R⁵ in a solvent, such as pyridine, at atemperature of from cooling with ice water to room temperature. Theurearization mentioned above can be attained by, for example, reactingthe resulting compound of the general formula (X) with sodium cyanate(NaOCN) at room temperature or under heating at, for example, 60° C. ina mixed solvent of water/acetic acid.

Alternatively, there is a method in which a racemic compound is obtainedby a brief process step using, in the place of the compound of thegeneral formula (II), the compound represented by the general formula(V) ##STR19## in which R^(1') and R^(2') have the same meanings as givenpreviously.

Thus, the compound represented by the above general formula (V) isreacted with the compound represented by the general formula (III) inwhich Y is hydrogen atom and the resulting ketoamine compound is, then,reduced, whereupon the protecting groups A, A",A"' and that forprotecting the amino group in the group R^(3') are de-protected, withthe proviso that the deprotection of the protecting group A isunnecessary for the case where R¹ stands for benzyloxy and theprotecting group A is benzyl, whereby the compound represented by thegeneral formula (I) in which R is hydrogen atom and R¹, R², R⁶, X, R⁷,R⁸, R⁹, *1 and *2 have the same meanings as those given previously isobtained.

The reaction of the compound of the general formula (V) with thecompound of the general formula (III) can be attained by the methoddisclosed in the literature, A. A. Larsen et al, J. Med. Chem., 10, 462(1967), with an improvement in such a manner that the reaction iseffected in a polar solvent, such as acetonitrile, dimethylformamide,dimethylacetamide or dimethylsulfoxide, in the presence or absence of anamine as the acid-capturing agent under cooling with ice water or withheating at a temperature up to 60° C., followed by reduction of thecarbonyl group using a reducing agent, such as sodium borohydride orsodium cyanoborohydride, under cooling with ice water or at roomtemperature, followed by deprotection of the protecting group. By thisreaction, a racemic mixture of *1 is obtained, so that an opticalresolution by the method as given afterwards becomes necessary forobtaining each optical active compound.

Production Process B

As an alternative production process in which each optical activecompound or racemic modification is obtained, a technique using anepoxide may be incorporated.

Thus, the compound represented by the general formula (I) in which R ishydrogen atom and R¹, R², R⁶, X, R^(7'), R^(8'), R^(9'), *1 and *2 havethe same meanings as those given previously can be produced by reactinga compound represented by the general formula (XII), ##STR20## in whichR', R^(2') and *1 have the meanings as those given previously, with thecompound represented by the general formula (III) in which Y denoteshydrogen atom and X, R⁶, R^(7'), R^(8'), R^(9') and *2 have the samemeanings as those defined previously, followed by deprotection of theprotecting groups A, A", A"', that for protecting the amino group in thesubstituent R³ and the protecting acetyl group for R^(1') by the methoddescribed in the paragraph "Production Process A", with the proviso thatthe deprotection of the protecting group A is unnecessary when R¹ isbenzyloxy and the protecting group A is benzyl.

The reaction of the compound represented by the general formula (XII)with the compound represented by the general formula (III) can becarried out in a usual organic solvent, for example, dimethylsulfoxide,a straight chained or cyclic ether, dimethylformamide ordimethylacetamide. While the compound represented by the general formula(XII) and that represented by the general formula (III) are used oftenin an equimolar proportion, it is preferable to use an excess of thecompound represented by the general formula (III) over the compound ofthe general formula (XII). The reaction is effected at an adequatetemperature and, usually, at room temperature or the reflux temperatureof the solvent employed. The reaction duration may be selected inaccordance with the reaction condition and other factors and, usually,the reaction can be terminated at the point at which the yield becomesmaximum.

It was reported that the yield of the reaction can be increased and thereaction duration is reduced by adding to the reaction mixturetrimethylsilylacetamide (TMSA) [N,O-bis(trimethylsilylacetamide)],hexamethyldisilazane (HMDS) or bis(trimethylsilyl)urea [TetrahedronLetters, 27, 2451 (1986)] and this may adequately be incorporatedherein.

The compound represented by the general formula (XII) is known and canbe synthesized by an ordinary method given in chemical literatures. Forexample, the general formula (XII) can be produced by oxidizing styreneor a substituted styrene derivative using a peracid, such asm-chloroperbenzoic acid, or by reacting dimethylsulfonium methylideordimethylsulfoxonium methylide with a substituted benzaldehyde having asubstituent group corresponding to R^(1') or R^(2'), as described in J.Am. Chem. Soc.,87, 1353 (1956).

An optical active compound represented by the general formula (XII) canbe produced by reducing the compound represented by the general formula(II) or a substituted mandelic acid derivative in which the α-carbonatom (*1) is in a desired absolute configuration into a correspondingglycol derivative, tosylating or mesylating or halogenating, then, theresulting primary alcohol and cyclizing the resulting compound using astrong base, such as an alkali metal hydroxide, under a usualintramolecular nucleophilic substitution reaction.

Production Process C

Alternatively further, there is a method for producing a racemicmodification by condensing a phenylglyoxal compound represented by thegeneral formula (XIII) ##STR21## in which R^(1') and R^(2') have thesame meanings as those given previously with an amine compoundrepresented by the general formula (III) in which Y is hydrogen atom andX, R⁶, R^(7'), R^(8'), R^(9') and *2 have the same meanings as thosegiven previously and reducing the resulting compound, with finaldeprotection of the protecting groups A, A", A"', the protecting groupfor the amino group of R^(3') and the protecting acetyl group of R^(1')by the procedure described in the paragraph of "Production Process A",with the proviso that the deprotection of the protecting group A isunnecessary when R¹ is benzyloxy and the protecting group A is benzyl.

This reaction is carried out in general in a reaction solvent byreducing the Schiff base resulting from the condensation reaction usingan adequate reducing agent capable of reducing the Schiff base and atthe same time reducing the oxo-group into hydroxyl group. As thereducing agent, there may be employed, for example, sodium borohydride,sodium cyanoborohydride and lithium cyanoborohydride. The proportion ofthe phenylglyoxal compound to the amine compound is in general 1-3moles, preferably 1-1,5 moles of the former to 1 mole of the aminecompound. Reaction may be carried out at an adequate temperature and, ingeneral, at a temperature from room temperature to the refluxtemperature of the solvent employed. The reaction duration mayadequately be chosen in accordance with the reaction condition and so onand may be terminated at a point at which the reaction yield becomeshighest. The above reactions may be carried out in a reaction solventbased on alcohol, such as methanol or ethanol, preferably at a lowtemperature in the presence of sodium borohydride.

The compound of the general formula (XIII) can be obtained easily byoxidizing an acetophenone derivative substituted by R^(1') and R^(2') ina reaction medium of water or an organic solvent, for example, acyclicether, such as dioxane or tetrahydrofuran, using an oxidizing agent,such as selenium dioxide. Alternatively, it can be produced by theprocess described in J. Am. Chem. Soc., 79, 6562 (1957).

Production Process D

The compound represented by the general formula (I) in which R ishydrogen atom and R¹, R², R⁶, X, R⁷, R⁸, R⁹, *1 and *2 have the samemeanings as those given previously can be obtained also by reacting anamine compound represented by the general formula (XIV), ##STR22## inwhich R^(1'), R^(2') and *1 have the same meanings as those givenpreviously, with a compound represented by the general formula (XV),##STR23## in which R⁶, X, R^(7'), R^(8'), R^(9') and *2 have the samemeanings as those given previously and Z denotes an eliminable group,followed by deprotection of the protecting groups A, A", A"', thatprotecting the amino group in R^(3') and the protecting acetyl group inR^(1') by the method described in the paragraph "Production Process A",with the proviso that the deprotection of the protecting group A isunnecessary when R¹ is benzyloxy and the protecting group A is benzyl.

By effecting the coupling reaction with the amine compound in an organicsolvent, if necessary, in the presence of a proton-acceptor, such as atertiaryamine, for example, triethylamine, the compound represented bythe general formula (I) is obtained. The "eliminable group" means agroup which is eliminated upon the above reaction of the chloride,bromide or iodide group or mesyl or tosyl group with, for example,sulfonate or so on. The reaction may be realized, for example, using, ingeneral, 1-10 moles of the amine compound represented by the generalformula (XIV) per one mole of the compound represented by the generalformula (XV).

Since this reaction proceeds at a lower velocity, the reaction maypreferably be effected in an autoclave in a reaction solvent, forexample, an alcohol, such as methanol, ethanol or butanol, a halogenatedhydrocarbon, such as methylene chloride or chloroform, ortetrahydrofuran or dioxane. The reaction temperature is chosen, ingeneral, in the range from 10 to 150° C., preferably from 70 to 130° C.The reaction duration is chosen, in general, in the range from 5 to 100hours.

The compound of the general formula (XIV) can be obtained byhydrogenating a substituted mandelonitrile substituted by R^(1') andR^(2') in the presence of a catalyst, such as Raney nickel. Thesubstituted mandelonitrile can be produced by a reaction of asubstituted benzaldehyde with hydrogen cyanide or with sodium cyanatetogether with sodium hydrogen sulfite as a racemic compound from whicheach optical active isomer can easily be separated by methods andtechniques employed commonly by preparing salts of the diastereomerswith an optically active acid selected adequately. The optically activesubstituted mandelonitrile derivative can be obtained by reacting theoptically active carboxylic acid resulting from hydrolysis of theoptically active substituted mandelonitrile with ammonia in the presenceof a commonly employed condensing agent, followed by reduction of theresulting product.

The compound of the general formula (XV) can be obtained by reacting aphenol compound represented by the general formula (VIII) with acompound represented by the general formula (XVI), ##STR24## in which R⁶and *2 have the same meanings as those given previously and B' is ahalogen atom, or with a compound represented by the general formula(XVII), ##STR25## in which R⁶ and *2 have the same meanings as thosegiven previously, under the condition of synthesizing the compoundrepresented by the general formula (III) described in the paragraph of"Production Process A", followed by tosylating or mesylating the alcoholresulting from the above reaction with the compound represented by thegeneral formula (XVI).

Production Process E

The compound represented by the general formula (I) in which R is methylcan be produced by methylating the alcohol compound of the generalformula (I) in which R is hydrogen atom produced by the "ProductionProcess" A, B, C or D under a commonly employed acidic condition. Thus,the compound of the general formula (I) in which R is methyl can beproduce by treating the compound of the general formula (I) in which Ris hydrogen atom with hydrogen chloride in methanol at a temperaturefrom room temperature to the boiling point of the reaction medium.

The compound represented by the general formula (XVIII), ##STR26## inwhich R^(1'), R^(2'), R⁶, Y', X, R^(7'), R^(8'), R^(9'), *1 and *2 havethe same meanings as those given previously, which is a compound inwhich the amino group of the amine compound formed in the process forproducing the compound represented by the general formula (I) in which Ris hydrogen atom is protected by the protecting group Y' and in which apossible protecting group A' for the hydroxyl group, if present, isde-protected by the method described above, is processed by methylationof the hydroxyl group by a commonly used technique. By de-protecting theprotecting group Y' for the amino group and those of A, A", A"' and thatprotecting the amino group in R^(3'), if present, as well as theprotecting acetyl group in R^(1'), with the proviso that thedeprotection of the protecting group A is unnecessary when R¹ isbenzyloxy and the protecting group A is benzyl, the compound representedby the general formula (I) in which R is methyl and R¹, R², R⁶, X, R⁷,R⁸, R⁹, *1 and *2 have the same meanings as those given previously isobtained.

A concrete example of methylation of the hydroxyl group consists in thatthe compound is reacted with 1-5 equivalents of methyl iodide or methylbromide in the presence of a base, such as potassium carbonate,triethylamine, sodium hydroxide or sodium hydride, in a solvent, such asdimethylsulfoxide, dimethylformamide, dimethoxyethane ortetrahydrofuran, at a temperature in the range from room temperature tothe reflux temperature of the solvent. An alternative embodimentconsists in that the compound is reacted, in a form of its alkalinesolution containing sodium hydroxide or potassium hydroxide in water orin methanol, with 2-10 equivalents of dimethyl sulfate at a temperaturein the range from room temperature to the reflux temperature of thesolvent.

The starting compounds of the present invention may, if necessary, bepurified, wherein known chromatographic techniques including column-,flush column-, thin layer- and high performance liquid chromatographymay be employed therefor by taking into account of such a parameter asthe Rf value given in this specification.

As described above, the compound represented by the general formula (I)may be present as four or two different isomers. The process accordingto the present invention can provide both the pure isomer and theracemic mixture. The reactions described above do not alter thepertaining stereo chemistry.

Therefore, starting from the compound of the general formula (V) or ofthe general formula (XIII) having no asymmetric carbon atom, startingfrom the racemic compound represented by the general formula ([I), (XII)or (XIV), or starting from the racemic compound represented by thegeneral formula (III) or (XV), isomeric mixtures (R,R), (R,S), (S,S) and(S,R) are obtained. Similarly, starting from the pure isomer of thegeneral formula (III) or (XV) and, for example, from the R-isomer of thegeneral formula (III), mixtures of only two isomers (R,R) and (S,R) areobtained and, if an optical active isomer of the general formula (II),(XII) or (XIV) is employed, corresponding pure isomer can be obtained.

When a mixture of the four isomers or of two isomers is obtained, theisomers can be separated by a pertinent technique, such as fractionalcrystallization or the like, as their addition salts with an opticallyactive acid, such as camphor sulfonic acid, mandelic acid or asubstituted mandelic acid. The fractional crystallization may beperformed using an adequate solvent, preferably a lower alkanol, such asethanol or isopropanol or a mixture of them.

Every pair of the enantiomers can be separated into each optical activeisomer by, for example, forming a diastereomeric salt andchromatographic separation on an optically active column, or by othermeans. When one of the starting raw materials is optically active, themixture of the diastereomers obtained as above can be divided into eachpure isomer. By separating each of the optical active isomers andpurifying it, it becomes possible to improve the pharmacological effector to eliminate side effects by using only the isomer having more higheractivity which is preferable as a medicament.

As the salt of the compound represented by the general formula (I)according to the present invention, there may be exemplified salts withknown acids, for example, addition salts thereof with mineral acids andorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogen sulfuric acid, dihydrogen phosphoric acid, citric acid,maleic acid, tartaric acid, fumaric acid, gluconic acid and methanesulfonic acid; and with optically active acids, such as camphor sulfonicacid, mandelic acid and substituted mandelic acids, wherein specialpreference is given to those which are medicamentally acceptable.

For preparing a salt of the compound represented by the general formula(I), the compound of the general formula (I) is dissolved in an alcohol,such as methanol or ethanol, and the acid component is added to theresulting alcoholic solution, whereby the corresponding acid additionsalt can be obtained. Examples of the acids to be used therefor includemineral acids and organic acids which are medicamentally acceptable,such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogensulfuric acid, dihydrogen phosphoric acid, citric acid, maleic acid,tartaric acid, fumaric acid, gluconic acid and methane sulfonic acid.

The tricyclic compounds and the pharmacologically acceptable saltsaccording to the present invention have no recognizable toxicity and areuseful as medicaments and exhibit, for example, β3-activity, so thatthey can be utilized as medicaments for therapeutic and preventivetreatments of β3-correlating diseases. The "β3-correlating diseases" isa generic expression for diseases which can be improved by a functionalactivity mediated β3-adrenaline receptor and include, for example,diabetes, obesity, hyperlipemia, diseases in digestive system, such asabnormal motion and ulcer in digestive system, and depression. Inparticular, the compound according to the present invention serves fortreating diabetes, obesity and hyperlipemia. Thus, the compoundaccording to the present invention is effective as a medicament forpreventive or therapeutic treatment of diabetes due to its function fordecreasing the blood sugar value and is also effective for preventivetreatment of hyperlipemia and therapeutic treatment of obesity due toits lipolytic activity.

In preparing a medicament from the compound according to the presentinvention, it is preferable to admix, if necessary, to an effectiveamount of the tricyclic compound represented by the general formula (I)or salt thereof a pharmacologically acceptable carrier to formulate adrug composition. As the pharmacologically acceptable carrier, there maybe exemplified excipients, binding agents, such ascarboxymethylcellulose etc., disintegrator, lubricants and variousadditives.

For administering the drug containing the compound according to thepresent invention to human, oral administration of the drug in a form oftablet, powder, granules, capsule, sugar-coated tablet, liquid drug orsyrup. Drugs for parenteral administration, such as injection drugs, mayalso be possible. The dose amount of administration may be different inaccordance with the age, body weight, significance of the disease,symptom and so on and the dose may, in general, be in an amount of0.01-2,000 mg per day for an adult all at once or allotted in severaladministrations. The term for receiving such drug may in general, rangefrom several weeks to several months with daily administration, while itis possible to increase or decrease both the term and the daily dose inaccordance with the state of the disease of patient.

THE BEST MODE FOR EMBODYING THE INVENTION

Below, the present invention will further be described by way ofExamples, wherein the present invention should not be understood asbeing restricted thereto.

For thin layer chromatography (TLC), Precoated Silica Gel 60 F254 (ofthe firm Merck) was employed. After development with a mixed solvent ofchloroform/methanol (100/1-4/1) or ethyl acetate/n-hexane (100/0-1/10),confirmation by UV-irradiation (254 nm) and color reaction withninhydrin was performed. The Rf values of TLC cited refer to those ofthe free amines. For drying the organic solvent, anhydrous magnesiumsulfate or anhydrous sodium sulfate was used. A silica gel(Wako-gelC-200, a product of Wako Pure Chemical Ind., Ltd.) was used for thecolumn chromatography and Silica Gel 60 (230-400 mesh, a product of thefirm Merck) was used for the flush column chromatography. Pre-CoatedSilica Gel 60 F254 (20×20 cm, 2 mm ; supplied from Merck) was used forthe parting thin layer chromatography. Elution was effected using amixed developer of chloroform/methanol (1/1).

For observing the nuclear magnetic resonance spectrum (NMR), Gemini-300(FT-NMR; of the firm Varian) was employed. As the solvent, heavychloroform was used so long as no special mention is made.Tetramethylsilane (TMS) was used as the internal standard for thechemical shift which was recorded in terms of (δ ppm). The couplingconstant is indicated by J(Hz). For observing mass spectrum (MS),JEOL-JMS-SX102 was employed and the observation was made by fast atombombardment mass spectrum (FAB-MS). The results of the tests aresummarized in Table 1.

EXAMPLE 1(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamidehydrochloride

A. Synthesis of 2-benzyloxycarbonylamino-1-bromoethane (Intermediate 0)

To a solution of 25 g of 2-bromoethylamine hydrochloride (supplied fromTokyo Chemical Industry Co.,Ltd.) and 34 ml of triethylamine in 450 mlof methylene chloride, 19 ml of benzyloxycarbonyl chloride were addeddropwise over a period of 20 minutes under cooling by ice water withagitation, whereupon the agitation was continued for further 19 hours.The reaction mixture was then rinsed with water, saturated aqueoussodium bicarbonate solution and saturated aqueous sodium chloridesolution successively, whereupon the organic layer was dried and thesolvent was evaporated off under a reduced pressure. The residue wascooled with ice water and the crystals were filtered off and washed withhexane. whereby 29.4 g of the above-identified compound were obtained.Rf=0.58 (chloroform).

B. Synthesis of 9H-2-(2-benzyloxycarbonylaminoethoxy)carbazole(Intermediate 1)

To a solution of 252 mg of 2-hydroxycarbazole(supplied from the firmAldrich) and 292 mg of potassium carbonate in 4 ml of dimethylformamide,452 mg of the above Intermediate 0 were added and the mixture was heatedat 70° C. for 72 hours. To the reaction mixture, ethyl acetate and waterwere added to effect extraction and the organic layer was rinsed withwater and dried, from which the solvent was distilled off under areduced pressure and the residue was purified by a column chromatography(with methanol/chloroform of 1/100), whereby 184.7 mg of theabove-identified compound were obtained. Rf=0.77 (methanol/chloroform of1/10).

C. Synthesis of 2-(9H-carbazol-2-yloxy)ethylamine (Intermediate 2)

To 620 mg of Intermediate 1, 5 ml of 30% solution of hydrogen bromide inacetic acid were added and the mixture was agitated at room temperaturefor 1.5 hours. To the reaction mixture, diethylether was added undercooling with ice water and the deposited precipitate was isolated byfiltration. Water and NaOH were added to adjust the pH of the resultingmixture at 10, whereupon the mixture was subjected to extraction withethyl acetate. The organic layer was dried and the solvent was distilledoff under a reduced pressure, whereby 311.3 mg of the above-identifiedcompound were obtained. Rf=0.08 (methanol/chloroform of 1/10).

D. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamidehydrochloride

To a solution of 500 mg of Intermediate 2 in a mixed solvent of 40 ml ofanhydrous acetonitrile and 4 ml of anhydrous dimethylformamide, 670 mgof 2-bromo-1-[4-benzyloxy-3-[(methylsulfonyl)amino]phenyl]ethanone(70%purity)(Intermediate 3) [prepared by the method reported by A. A. Larsenet al, J. Med. Chem., 10, 462-472 (1967)] were added and the mixture wasagitated under argon atmosphere at 0° C. for 83 minutes.

This mixture was warmed to the room temperature(ca. 22° C.) and wasagitated for 79 minutes. To this mixture, a solution of 352 mg of sodiumborohydride in 30 ml of anhydrous ethanol were added at roomtemperature. After agitation for 81 minutes, the reaction was terminatedusing 1.0 N hydrochloric acid (pH 4) and thereto was added 0.89 g ofethanolamine. After agitation for 10 minutes, the mixture was dilutedwith 100 ml of ethyl acetate and the organic layer was rinsed withsaturated aqueous sodium chloride solution (three times with each 100ml) and was dried and concentrated under a reduced pressure to obtain1.09 g of a crude product.

This was purified by a column chromatography (ethyl acetate--1/8:methanol/chloroform), whereby 195 mg of the above-identified compound asfree amine were obtained. Rf=0.41 (methanol/chloroform of 1/10). To apart of this compound, 1.1 eq. of 0.1 N HCl/ethanol were added toconvert it into hydrochloride salt(the above-identified compound as freeamine were obtained. Rf=0.41 (methanol/chloroform Diethyl ether wasadded to the residue and the deposited precipitate was isolated byfiltration, washed with diethyl ether, dried under a reduced pressure at50° C., whereby 48.5 mg of the above-identified compound were obtainedas a powdery product.

EXAMPLE 2(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

753 mg of hydrochloride salt of the compound of Example 1 were subjectedto hydrogenolysis using 406 mg of 10% palladium/carbon black (suppliedfrom Merck) and 85 ml of methanol under 1 atm hydrogen gas (roomtemperature, 2.5 hours). The catalyst was filtered off on celite andwashed with chloroform and methanol. The filtrate and the washed liquorwere brought together and the solvent was distilled off under a reducedpressure, whereby 520 mg of the above-identified compound were obtainedas a pale yellow powdery product. Rf=0.11 (methanol/chloroform of 1/10).

EXAMPLE 3(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamide

A. Synthesis of 3-hydroxydibenzofuran

To a solution of 1 g of 3-methoxydibenzofuran (provided from the firmSALOR) in 5 ml of methylene chloride, 10.2 ml of 1 M solution of borontribromide in methylene chloride were added dropwise. The reactionmixture was agitated for 30 minutes under cooling with ice water and,then, warmed to room temperature and agitated further 35 minutes.Thereto were added 26 ml of water all at once and the mixture was causedto temperature elevation up to room temperature over a period of 30minutes with vigorous agitation. The organic layer was separated off andthe aqueous layer was extracted twice with methylene chloride. Theunited organic phase was rinsed with saturated aqueous sodium chloridesolution and dried and was then concentrated under a reduced pressure toobtain 663.1 mg of the above-identified compound.

B. Synthesis of 3-(2-benzyloxycarbonylaminoethoxy)dibenzofuran(Intermediate 4)

Following the procedures given in the step B of Example 1, 321.3 mg of3-hydroxydibenzofuran, 541 mg of Intermediate 0 and 1,2 g of potassiumcarbonate were brought into reaction in 4.5 ml of dimethylformamide.Thereto were added ethyl acetate and water to effect extraction and theorganic layer was rinsed with water and dried, from which the solventwas distilled off under a reduced pressure and the residue was purifiedby a column chromatography (chloroform), whereby 574.2 mg of theabove-identified compound were obtained. Rf=0.40 (chloroform).

C. Synthesis of 2-(dibenzofuran-3-yloxy)ethylamine (Intermediate 5)

Following the procedures of step C in Example 1, 7 ml of 30% solution ofhydrogen bromide in acetic acid were added to 554.7 mg of Intermediate 4and the mixture was agitated at room temperature for 1 hour. Thereto wasadded diethyl ether under cooling with ice and the deposited precipitatewas isolated by filtration. Thereto were added water and NaOH to adjustthe pH of the mixture at 10, whereupon the mixture was subjected toextraction with ethyl acetate. The organic layer was dried and thesolvent was distilled off under a reduced pressure, whereby 224.6 mg ofthe above-identified compound were obtained. Rf=0.13(methanol/chloroform of 1/10).

D. Synthesis of(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamide

By a modification of the procedures described in the step D of Example1, a solution of 227 mg of Intermediate 3 (70% purity) was added to asolution of 91.6 mg of Intermediate 5 in a mixed solvent composed of 4ml of anhydrous acetonitrile and 1 ml of anhydrous dimethylformamideunder argon atmosphere at 0° C. and thereto were further added 56.3 μlof triethylamine, whereupon the resulting mixture was warmed to the roomtemperature (ca. 22° C.) and was agitated for 50 minutes. To thismixture, a solution of 80 mg of sodium borohydride in 4 ml of anhydrousethanol was added at room temperature. After agitation for 77 minutes,the reaction was terminated using 1 N hydrochloric acid (pH 4) andthereto were added 123 μl of ethanolamine. After agitation for 10minutes, the mixture was diluted with ethyl acetate and the organiclayer was rinsed thrice with saturated aqueous sodium chloride solutionand was dried and concentrated under a reduced pressure to obtain acrude product. This was purified by a column chromatography(chloroform--3/100: methanol/chloroform), whereby 52.4 mg of theabove-identified compound were obtained. Rf=0.37 (methanol/chloroform of3/100).

EXAMPLE 4(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

Following the procedures of Example 2, 52.4 mg of the compound ofExample 3 were subjected to a hydrogenolysis under 1 atm hydrogen gasusing 30 mg of 10% palladium/carbon black and 6.4 ml of methanol with4.7 μl of acetic acid (room temperature, 1 hour). The catalyst wasfiltered off on celite and was then washed with chloroform and methanol.The filtrate and the washed liquor were brought together, from which thesolvent was distilled off. To the resulting residue, ethyl acetate andsaturated aqueous sodium bicarbonate solution were added to carry outextraction and the organic layer was dried, from which the solvent wasdistilled off under a reduced pressure. The resulting product wasconverted into hydrochloride salt by adding thereto 1.1 eq. of 0.1 Nhydrochloric acid/ethanol, whereby 43.3 mg of the above-identifiedcompound were obtained as a pale orange powdery product.Rf=0.07(methanol/chloroform of 1/10).

EXAMPLE 5(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

2-bromo-1-[4-fluoro-3-[(methylsulfonyl)amino]phenyl]ethanone wasprepared in accordance with the procedures for the synthesis ofIntermediate 3 (with subsequence steps A, B, C and D).

A. Synthesis of 1-(4-fluoro-3-nitrophenyl)ethanone (Intermediate 6)

13.8 g of 4'-fluoroacetophenone (provided from Tokyo Chemical IndustryCo., Ltd.) were added in two portions to 100 ml of fuming nitric acidcooled to -10° C. with agitation. After the mixture was warmed to roomtemperature, the agitation was continued for further 4 hours. Thismixture was poured into 1.0 liter of ice water and was extracted with500 ml of ethyl acetate. The organic layer was dried and the solvent wasdistilled off under a reduced pressure. The residue was purified by acolumn chromatography (9/1-4/1: n-hexane/ethyl acetate) twice, whereby4.16 g of the above-identified were obtained. Rf=0.50 (chloroform).

B. Synthesis of 1-(3-amino-4-fluorophenyl)ethanone (Intermediate 7)

To a solution of 4.16 g of Intermediate 6 in 305 ml of methanol whichhad been purged with argon, 189.7 mg of palladium oxide were added andthe mixture was subjected to reduction under 1 atm hydrogen gas at roomtemperature. After agitation for 6 hours, the reaction system wasreplaced with argon and the reaction mixture was diluted with chloroformand was filtered. The solvent was evaporated off under a reducedpressure, whereby 3.52 g of the above-identified compound were obtained.Rf=0.47 (ethyl acetate/n-hexane of 1/1).

C. Synthesis of 1-[4-fluoro-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 8)

To a solution of 3.48 g of the Intermediate 7 in 100 ml of pyridine,1.93 ml of methanesulfonyl chloride were added at room temperature.After agitation for 2.5 days, the reaction mixture was poured intosaturated aqueous ammonium chloride solution and was subjected toextraction with 200 ml of ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride solution (three times with 100ml) and dried and the solvent was distilled off under a reduced pressureto obtain a crude product. This was purified by a column chromatography(1/1 of n-hexane/ethyl acetate), whereby 3.9 g of the above-identifiedcompound were obtained. Rf=0.23 (ethyl acetate/n-hexane of 1/1).

D. Synthesis of2-bromo-1-[4-fluoro-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 9)

To a solution of 3.9 g of Intermediate 8 in 50 ml of 1,4-dioxane, 2.83 gof bromine were added with agitation. The resulting mixture was warmedto 60° C. and was agitated for 1 hour. After having been cooled to roomtemperature, the mixture was subjected to evaporation under a reducedpressure. Water was added to the resulting residue and the depositedprecipitate was crushed and was filtered off, which was washed with coldethanol. After drying and recrystallization from ethanol, 3.69 g of theabove-identified compound were obtained. Rf=0.30 (with thricedevelopments; ethyl acetate/n-hexane of 1/2).

E. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethy]-2-fluorophenyl]methanesulfonamidehydrochloride

According to a modification of procedures described in the step D ofExample 1, a solution of 310 mg of Intermediate 9 in 3 ml of anhydrousacetonitrile was added to a solution of 226 mg of Intermediate 2 in amixed solvent composed of 20 ml of anhydrous acetonitrile and 2 ml ofanhydrous dimethylformamide under argon atmosphere at 0° C. and theretowere added 103 μl of triethylamine, whereupon the mixture was warmed tothe room temperature (ca. 22° C.) and was agitated for 50 minutes.

To this mixture was added a solution of 189 mg of sodium borohydride in15 ml of anhydrous ethanol at room temperature. After agitation for 77minutes, the reaction was terminated using 1 N hydrochloric acid (pH 4)and, then, 479 μl of ethanolamine were added thereto. After agitationfor 10 minutes, the resulting mixture was diluted with ethyl acetate andthe organic layer was rinsed with saturated aqueous sodium chloridesolution three times, whereupon it was dried and subjected toevaporation under a reduced pressure to obtain a crude product. This waspurified by a column chromatography (chloroform--3/100:methanol/chloroform), whereby 239.8 mg of free amine product of theabove-identified compound were obtained. To this product, 1.1 eq. of 0.1N hydrochloric acid/ethanol were added to convert it into hydrochloridesalt (the above-identified compound) and the solvent was distilled offunder a reduced pressure. Diethyl ether was added to the resultingresidue and the deposited precipitate was filtered off, followed bywashing with hot ethanol and drying at 50° C. under reduced pressure toobtain 121.1 mg of the above-identified compound as a powdery product.Rf=0.37 (methanol/chloroform of 1/6).

EXAMPLE 6(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

2-bromo-1-[4-chloro-3-[(methylsulfonyl)amino]phenyl]ethanone wasprepared in a manner similar to the synthesis method of Intermediate 3and in the same manner as in the steps A, B, C and D of Example 5.

A. Synthesis of 1-(4-chloro-3-nitrophenyl)ethanone (Intermediate 10)

15.5 g of 4'-chloroacetophenone (Tokyo Chemical Industry Co.,Ltd.) wereadded in two portions to 100 ml of fuming nitric acid cooled to -10° C.with agitation. The resulting mixture was warmed to room temperature andwas agitated for four hours. This mixture was poured into 1.6 liters ofice water and was then subjected to extraction with 800 ml of ethylacetate. The organic layer was separated and dried and the solvent wasevaporated off under a reduced pressure. The resulting residue waspurified by a column chromatography (9/1-4/1: n-hexane/ethyl acetate),whereby 1.2 g of the above-identified compound were obtained. Rf=0.52(chloroform).

B. Synthesis of 1-(3-amino-4-chlorophenyl)ethanone (Intermediate 11)

To a solution of 1.2 g of Intermediate 10 in 260 ml of methanol, 7.63 gof tin (II) chloride and 5.48 ml of concentrated hydrochloric acid wereadded and the mixture was agitated at room temperature for 3.5 hours.The mixture was concentrated and washed with saturated aqueous sodiumbicarbonate solution and was then subjected to extraction with ethylacetate. The organic layer was concentrated under a reduced pressure,whereby 970 mg of the above-identified compound were obtained. Rf=0.49(ethyl acetate/n-hexane of 1/1).

C. Synthesis of 1-[4-chloro-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 12)

To a solution of 970 mg of the Intermediate 11 in 50 ml of pyridine, 487μl of methanesulfonyl chloride were added at room temperature. Afteragitation for 2.5 days, the reaction mixture was poured into saturatedaqueous ammonium chloride solution and was subjected to extraction with100 ml of ethyl acetate. The organic layer was rinsed with saturatedaqueous sodium chloride solution (three times with 50 ml) and dried andconcentrated under a reduced pressure to obtain a crude product. Thiswas purified by a column chromatography (n-hexane/ethyl acetate of3/2-1/1), whereby 890 mg of the above-identified compound were obtained.Rf=0.41 (ethyl acetate/n-hexane of 1/1).

D. Synthesis of2-bromo-1-[4-chloro-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 13)

To a solution of 890 mg of Intermediate 12 in 10 ml of 1,4-dioxane. 605mg of bromine were added with agitation. The resulting mixture waswarmed to 60° C. and was agitated for 1 hour.

After having been cooled to room temperature, the mixture wasconcentrated under a reduced pressure. Water was added to the resultingresidue and the deposited precipitate was crushed and filtered off,which was washed with cold ethanol. After drying and recrystallizationfrom ethanol, 620 mg of the above-identified compound were obtained.Rf=0.39 (ethyl acetate/n-hexane of 1/1).

E. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethy]-2-chlorophenyl]methanesulfonamidehydrochloride

According to a modification of procedures described in the step D ofExample 1, a solution of 327 mg of Intermediate 13 in 3 ml of anhydrousacetonitrile was added to a solution of 226 mg of Intermediate 2 in amixed solvent composed of 20 ml of anhydrous acetonitrile and 2 ml ofanhydrous dimethylformamide under argon atmosphere at 0° C. and theretowere added 103 μl of triethylamine, whereupon the mixture was warmed tothe room temperature (ca. 22° C.) and was agitated for 50 minutes.

To this mixture was added a solution of 189 mg of sodium borohydride in15 ml of absolute ethanol at room temperature. After agitation for 77minutes,the reaction was terminated using 1 N hydrochloric acid (pH 4)and, then, 479 μl of ethanolamine were added thereto. After agitationfor 10 minutes, the resulting mixture was diluted with ethyl acetate andthe organic layer was rinsed with saturated aqueous sodium chloridesolution three times, whereupon it was dried and subjected toevaporation under a reduced pressure to obtain a crude product. This waspurified by a column chromatography (1/9-1/6 : methanol/chloroform),whereby 129.8 mg of free amine product of the above-identified compoundwere obtained. Rf=0.36 (methanol/chloroform of 1/6).

To this product, 1.1 eq. of 0.1 N hydrochloric acid/ethanol were addedto convert it into hydrochloride salt (the above-identified compound)and the solvent was distilled off under a reduced pressure. Diethylether was added to the resulting residue and the deposited precipitatewas filtered off, followed by washing with hot ethanol and drying at 50°C. under reduced pressure to obtain 34.1 mg of the above-identifiedcompound as a powdery product.

EXAMPLE 7(±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

To a solution of 219.5 mg of Intermediate 2 in a mixed solvent of 20 mlof anhydrous acetonitrile and 2 ml of anhydrous dimethylformamide, 163.6mg of 2-bromo-1-[3-(methylsulfonyl)aminophenyl]ethanone (Intermediate14) [prepared by the method reported by A. A. Larsen etal, J. Med.Chem., 9, 88-97 (1966)] were added and the mixture was agitated underargon atmosphere at 0° C. for 83 minutes.

This mixture was warmed to the room temperature(ca. 22° C.) and wasagitated for 79 minutes. To this mixture, a solution of 110 mg of sodiumborohydride in 10 ml of absolute ethanol were added at room temperature.After agitation for 81 minutes, the reaction was terminated using 1.0 Nhydrochloric acid (pH 4) and thereto was added 0.28 ml of ethanolamine.After agitation for 10 minutes, the mixture was diluted with 30 ml ofethyl acetate and the organic layer was rinsed with saturated aqueoussodium chloride solution three times and was dried and concentratedunder a reduced pressure to obtain 399 mg of a crude product. This waspurified by a PTLC (developed with methanol/chloroform of 1/8), whereby48.3 mg of the free amine were obtained. Rf=0.32 (methanol/chloroform of1/4).

1.1 eq. of 0.1 N HCl/ethanol were added to convert it into hydrochloridesalt (the above-identified compound) and the solvent was distilled offunder a reduced pressure. Diethyl ether was added to the residue and thedeposited precipitate was recrystallized from diethyl ether and driedunder a reduced pressure at 50° C., whereby 38.7 mg of theabove-identified compound were obtained as a powdery product.

EXAMPLE 8(±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]phenylmethanesulfonamidehydrochloride

A. Synthesis of 1-[3-benzylsulfonylamino)phenyl]ethanone (Intermediate15)

Following the procedures of synthesis of Intermediate 14 in Example 7,719 mg of the above-identified compound were prepared from 300 mg of3'-aminoacetophenone (Tokyo Chemical Industry Co., Ltd.), 427 mg ofbenzylsulfonylchloride (Tokyo Chemical Industry Co., Ltd.) and 3 ml ofpyridine.

B. Synthesis of 2-bromo-1-[3-(benzylsulfonylamino)phenyl]ethanone(Intermediate 15-1)

Following the procedures of Example 7, 130 μl of bromine were added to asolution of 700 mg of the Intermediate 15 in 6.8 ml of 1,4-dioxane tocause reaction, whereby a fraction containing the above-identifiedcompound (786 mg) was obtained. This showed in ¹ H-NMR (300 MHz, CDCl₃)a integrated ratio of 29% of the monobromide isomer, 58% of dibromideisomer and 13% of unreacted starting compound. The product was served inthe form of mixture as such for the subsequent reaction.

C. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]phenylmethanesulfonamidehydrochloride

A solution of 465 mg of Intermediate 15-1 (58%purity) in 10 ml ofanhydrous acetonitrile was added to a solution of 400 mg of Intermediate2 in a mixed solvent composed of 40 ml of anhydrous acetonitrile and 4ml of anhydrous dimethylformamide under argon atmosphere at 0° C. andthe mixture was agitated for 80 minutes.

The mixture was warmed to the room temperature (ca. 22° C.) and wasagitated for further 70 minutes. To this mixture was added a solution of244 mg of sodium borohydride in 20 ml of absolute ethanol at roomtemperature. After agitation for 60 minute, the reaction was terminatedusing 1.0 N hydrochloric acid (pH 4) and thereto was added ethanolamine.After agitation for 10 minutes, the mixture was diluted with 60 ml ofethyl acetate and was rinsed with 60 ml of water, whereupon the organiclayer was washed twice with saturated aqueous sodium chloride solutionand was, after drying, subjected to evaporation under a reduced pressureto obtain a crude product. This was purified by a PTLC (developed withmethanol/chloroform of 1/8), whereby 66 mg of free amine compound wereobtained. Rf=0.16 (methanol/chloroform of 1/10).

This was converted into hydrochloride salt (the above-identifiedcompound)by adding 1.1 eq. of 0.1 N hydrogen chloride/ethanol, whereuponthe solvent was distilled off under a reduced pressure. To the residuewas added diethyl ether and the deposited precipitate was washed withdiethyl ether and dried at 46° C. under a reduced pressure, whereby 60mg of the above-identified compound were obtained as a powdery product.

EXAMPLE 9(±)-N-[3-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

Following the procedures of Example 7, the above-identified compound wassynthesized from 224.6 mg of Intermediate 5 and 170 mg of Intermediate14, with the proviso that the following modification was incorporated.Thus, addition of dimethylformamide was omitted and the purification ofthe crude product was effected twice by a chromatography(methanol/chloroform of 1/20-1/10). The free amine compound (98.4 mg)was converted into its hydrochloride salt (the above-identifiedcompound) with 1.1 eq. of 0.1 N hydrogenchloride/ethanol, whereupon thesolvent was evaporated off under a reduced pressure. To the resultingresidue was added diethyl ether and the deposited precipitate was washeddiethyl ether and dried under a reduced pressure at 46° C., whereby theabove-identified compound was obtained as a powdery product. Rf=0.27(methanol/chloroform of 1/10).

EXAMPLE 10(±)-N-[3-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

A. Synthesis ofN-[7-[2-[(benzyloxycarbonyl)amino]ethoxy]-9H-fluoren-2-yl]acetamide(Intermediate 16)

Following the procedures of the step B of Example 1, 300 mg of2-acetamide-7-hydroxyfluorene (supplied from the firm SALOR), 485,5 mgof Intermediate 0 and 241.2 mg of potassium carbonate were brought intoreaction in 3 ml of dimethylformamide (heated at 70° C. for 24 hours).To the reaction mixture, ethyl acetate and water were added to subjectto extraction and the organic layer was rinsed with water and dried,whereupon the solvent was distilled off and the residue was purified bya column chromatography (methanol/chloroform of 1/20) to obtain 431.9 mgof the above-identified compound. Rf=0.47 (methanol/chloroform of 1/10).

B. Synthesis of N-[9H-7-(2-aminoethoxy)fluorene]-2-acetamide(Intermediate 17)

Following the procedures of step C of Example 1, 5 ml of 30% solution ofhydrogen bromide in acetic acid were added to 572.9 mg of Intermediate16 and the mixture was agitated at room temperature for 1 hour. Theretowas added diethyl ether under cooling with ice and the depositedprecipitate was isolated by filtration. Water and NaOH were added toadjust the pH of the mixture at 10, whereupon the mixture was subjectedto extraction with ethyl acetate. The organic layer was dried and thesolvent was distilled off under a reduced pressure, whereby 256.7 mg ofthe above-identified compound were obtained. Rf=0.06(methanol/chloroformof 1/5).

C. Synthesis of(±)-N-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

Following the procedures of Example 7, the above-identified compound wassynthesized from 253.2 mg of Intermediate 17 and 154.1 mg ofIntermediate 14, with the proviso that the following modification wasincorporated. Thus, addition of dimethylformamide was omitted and thepurification of the crude product was effected by a chromatography(methanol/chloroform of 1/10) and a PTLC (development withmethanol/chloroform of 1/5). The free amine compound (52.3 mg) wasconverted into its hydrochloride salt (the above-identified compound)with 1.1 eq. of 0.1 N hydrogen chloride/ethanol, whereupon the solventwas evaporated off under a reduced pressure. To the resulting residuewas added diethyl ether and the deposited precipitate was washed diethylether and dried under a reduced pressure at 46° C., whereby theabove-identified compound (45.1 mg) was obtained as a powdery product.Rf=0.40 (methanol/chloroform of 1/5).

EXAMPLE 11(±)-N-[3-[2-[[1-(9H-carbazol-2-yloxy)propan-2R-yl]amino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

A. Synthesis of (R)-[1-(9H-carbazol-2-yloxy)propan-2-yl]amine(Intermediate 18)

4.82 g of (R)-(-)-2-amino-1-propanol (supplied from the firm Aldrich)were dissolved in 157 ml of tetrahydrofuran and thereto were added 13.84g of di-tert-butyl-dicarbonate at room temperature and the mixture wasagitated for 18 hours. The solvent was evaporated off under a reducedpressure to obtain 11 g of a white solid product.

10.3 g of the above white solid product were dissolved together with17.76 g of triphenylphosphine in 147 ml of methylene chloride, whereto9.3 g of N-chlorosuccinimide were added in small portions underice-cooling and the mixture was agitated at room temperature for 23hours. The reaction liquor was washed with an aqueous sodium hydroxideand saturated aqueous sodium chloride solution successively, followed bydrying and distilling off of the solvent under a reduced pressure. Theresidue was purified by a silica gel chromatography, whereby 5.89 g of(R)-2-(N-tert-butoxycarbonyl)amino-1-chloropropane were obtained.Rf=0.89 (methanol/chloroform of 1/9).

To a solution of 734 mg of 2-hydroxycarbazole and 815.6 mg of the abovecompound in 9.6 ml of dimethylformamide, 1,588 mg of anhydrous potassiumcarbonate and 190 mg of potassium iodide were added and the reaction andthe after-treatment were performed in accordance with the procedures ofthe synthesis method in the step B of Example 1, whereby 597 mg of(R)-2-(N-tert-butoxycarbonylamino-1-propyloxy)carbazole were obtained.Rf=0.81 (methanol/chloroform of 1/9).

To 597 mg of the above compound were added 10 ml of 30% solution ofhydrogen bromide in acetic acid and the reaction and after-treatmentwere effected in accordance with the procedures of the synthetic methodin the step C of Example 1, whereby 258 mg of Intermediate 18 wereobtained. Rf=0.06 (methanol/ethyl acetate of 1/10).

B. Synthesis of(±)-N-[3-[2-[[1-(9H-carbazol-2-yloxy)propan-2R-yl]amino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The above-identified compound was synthesized in accordance with theprocedures of Example 7 by performing the reaction of the Intermediate18 (120 mg) with Intermediate 14 (190 mg) and the after-treatments, withthe proviso that the following alterations were incorporated. Thus, inthe coupling reaction, 72 μl (1 eq.) of triethylamine were used as thebasic catalyst and the purification of the crude product was effected bya PTLC (with development with methanol/ethyl acetate of 1/9). The freeamine compound (87.5 mg) was converted into its hydrochloride salt (theabove-identified compound) using 1.1 eq. of 0.1 N solution of hydrogenchloride/ethanol and the solvent was distilled off under a reducedpressure. To the residue was added diethyl ether and the depositedprecipitate was washed with diethyl ether and dried at 46° C. under areduced pressure, whereby 80.5 mg of the above-identified compound wasobtained as a powdery product. Rf=0.19 (methanol/ethyl acetate of 1/10).

EXAMPLE 12(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

A. Synthesis of (R)-2-bromo-1-[3-nitro-4-(benzyloxy)phenyl]ethanol(Intermediate 19)

To a solution of 1.01 g of2-bromo-1-[3-nitro-4-(benzyloxy)phenyl]ethanone (70% purity) preparedaccording to the method reported by C. Kaiser et al in J. Med. Chem.,17, 49 (1974) and 100 mg of(R)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrolo[1,2-c][1.3.2]oxazaborol[a product of Tokyo Chemical Industry Co., Ltd., referred to hereinafteras the "asymmetric catalyst"; there are (R)- and (S)-modifications] in20 ml of anhydrous tetrahydrofuran (prepared upon use), 2.16 ml of a 2 Msolution of borane/dimethylsulfide complex in tetrahydrofuran (suppliedfrom the firm Aldrich) were added dropwise over a period of 5 minutesand the mixture was agitate at the same temperature for 2 hours.

The reaction mixture was diluted with ethyl acetate and the so-dilutedmixture was washed with saturated aqueous ammonium chloride solution andsaturated aqueous sodium chloride successively, followed by drying andevaporating off of the solvent under a reduced pressure. The residue waspurified by a column chromatography (ethyl acetate/n-hexane of 1/2-1/1),whereby 1.015 g of the above-identified compound were obtained. Rf=0.41(ethyl acetate/n-hexane of 1/1).

Retention time: 35.7 min. Analytical conditions: column: CHIRALCEL OB(4.6 mm φ, 25 cm long; supplied from Daicel Chem. Ind., Ltd.). Mobilephase: n-hexane/2-propanol (7/3); flow rate: 0.5 ml/min. detection wavelength: 254 nm; temperature: 35° C.

B. Synthesis of(R)-3-nitro-4-benzyloxy-[2-iodo-1-(triethylsilyloxy)ethyl]benzene(Intermediate 20)

To a solution of 695,6 mg of Intermediate 19 in 30 ml of acetone, 2.96 gof sodium iodide (supplied from Wako Pure Chemical Ind., Ltd.) wereadded and the mixture was heated under reflux for 2 hours. After coolingto room temperature, the mixture was treated by filtration and thesolvent in the filtrate was evaporated off under a reduced pressure. Tothe resulting residue, chloroform and water were added and the organiclayer was rinsed with saturated aqueous sodium thiosulfate solution andwas dried, whereupon the solvent was evaporated off under a reducedpressure. The resulting oily product (0.78 g), imidazole (408.5 mg) anddimethylaminopyridine (24.4 mg) were dissolved in 5 ml ofdimethylformaide, whereto 452 mg of triethylsilane chloride were addedunder ice-cooling. Directly thereafter, the mixture was warmed to roomtemperature and was agitated for 1.5 hours. The resulting mixture wasdiluted with ethyl acetate and then rinsed with water, 2% aqueous coppersulfate solution, water and, finally, saturated aqueous sodium chloridesolution successively, followed by drying and distilling off of thesolvent under a reduced pressure. The residue was purified by a columnchromatography (ethyl acetate/n-hexane of 1/3), whereby 915 mg of theabove-identified compound were obtained. Rf=0.76(ethyl acetate/n-hexaneof 1/1).

C. Synthesis of(R)-N,N-[[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-[3-nitro-4-(benzyloxy)phenyl]]ethyl]amine(Intermediate 21)

A solution of 289 mg of Intermediate 20, 165 mg of Intermediate 2 and0.51 ml of Huenig base (supplied from the firm Aldrich) in 1.5 ml ofdimethylacetamide was agitated for 8 hours at 60° C. To the resultingreaction mixture, 40 ml of ethyl acetate and 40 ml of water were addedto effect extraction, whereupon the aqueous layer was further extractedwith ethyl acetate three times. The united organic phase was dried andthe solvent was distilled off under a reduced pressure. The residue waspurified by a column chromatography(chloroform--methanol/chloroform=1/49), whereby 173 mg of theabove-identified compound were obtained. Rf=0.60 (methanol/chloroform of1/9).

D. Synthesis of(R)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-[3-nitro-4-(benzyloxy)phenyl]]ethyl]amine(Intermediate 22)

173 mg of the above amine compound were dissolved in 2 ml of methylenechloride and thereto were added 45 μl of triethylamine and the mixturewas agitated under ice-cooling and thereto were added 43 μl ofbenzylchloroformate (supplied from the firm Aldrich). After agitationfor 30 minutes, the mixture was agitated for 8 hours at roomtemperature. The mixture was then diluted with ethyl acetate and rinsedwith water and,then, with saturated aqueous sodium chloride solution,successively, followed by drying and distilling off of the solvent undera reduced pressure. The residue was purified by a column chromatography(ethyl acetate/n-hexane=1/5-1/3), whereby 200 mg of the above-identifiedcompound were obtained. Rf=0.55 (ethyl acetate/n-hexane of 1/2).

Retention time: 14.7 min. Analytical conditions: column CHIRALCEL OJ-R(4.6 mmφ, 15 cm long; supplied from Daicel. Chem. Ind., Ltd.); mobilephase: 0.5 M NaClO₄ /CH₃ CN=20/80; flow rate: 0.7 ml/min.; detectionwave length: 254 mm; temperature: 30° C.

E. Synthesis of(R)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-[3-amino-4-(benzyloxy)phenyl]]ethyl]amine(Intermediate 23)

To a solution of 200 mg of the above nitro compound in 14 ml of methanolwhich had been purged by argon, 5 mg of platinum oxide (anhydrous,supplied from Wako Pure Chem. Ind., Ltd.) were added and the compoundwas reduced under 1 atm. hydrogen gas under ice-cooling. After agitationfor 6 hours, the reaction system was replaced by argon and the reactionmixture was diluted with chloroform and filtered. The solvent wasevaporated under reduced pressure, whereby 183 mg of theabove-identified compound were obtained. Rf=0.32 (ethyl acetate/n-hexaneof 1/3).

F. Synthesis of(R)-N-[5-[2-[benzyloxycarbonyl-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(triethylsilyloxy)ethyl]-2-(benzyloxy)phenyl]methanesulfonamide(Intermediate 24)

To a solution of 183 mg of the above amine compound in 1 ml of pyridine,20 μl of methanesulfonyl chloride were added and the mixture wasagitated for 1 hours, whereto water was added and the resulting mixturewas agitated for 3 hours, before the mixture was ice-cooled and thethereby deposited precipitate was separated by filtration. Theprecipitate was dissolved in ethyl acetate and the organic layer wasrinsed with saturated aqueous sodium chloride solution and dried,whereupon the solvent was distilled off under a reduced pressure toobtain 192 mg of the above-identified compound. Rf=0.44 (ethylacetate/n-hexane of 1/2).

G. Synthesis of(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

In accordance with the procedures of the step C in Example 1, thebenzyloxycarbonyl group and the triethylsilyl group were eliminatedusing 192 mg of the above methanesulfonamide compound with 4 ml of 30%solution of hydrogen bromide in acetic acid. Then, in accordance withthe procedures of the step E in Example 1, the benzyl group wassubjected to hydrogenolysis under a hydrogen atmosphere using 71 mg of10% palladium carbon black (supplied from Merk), followed by conversioninto hydrochloride salt by means of a usual technique, whereby theabove-identified compound was obtained.

Retention time: 40.6 min. Analytical conditions: column CHIRALCEL OJ-R(supplied from Daicel Chem. Ind., Ltd.); mobile phase 0.5 M NaClO₄ /CH₃CN=77/23; flow rate: 0.5 ml/min.; detection wave length: 254 nm;temperature: 40° C.

EXAMPLE 13(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

The reactions and the after-treatments were performed in the same manneras in Example 12, except that an asymmetric catalyst of (S)-modification(supplied from Tokyo Chemical Industry Co.,Ltd.) was used.

A. Synthesis of (S)-2-bromo-1-[3-nitro-4-(benzyloxy)phenyl]ethanol

Retention time: 47.3 min. Analytical conditions: column CHIRALCEL OB(supplied from Daicel Chem. Ind., Ltd.); mobile phasen-hexane/2-propanol=7/3; flow rate: 0.5 ml/min.; detection wave length:254 nm; temperature: 35° C.

D. Synthesis of(S)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-[3-nitro-4-(benzyloxy)phenyl]]ethyl]amine

Retention time: 9.8 min. Analytical conditions: column CHIRALCEL OJ-R(supplied from Daicel Chem. Ind., Ltd.); mobile phase 0.5 M NaClO₄ /CH₃CN=2/8; flow rate: 0.7 ml/min.; detection wave length: 254 mm;temperature: 30° C.

G. Synthesis of(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

Retention time: 47.5 min. Analytical conditions: column: CHIRALCEL OJ-R(supplied from Daicel Chem. Ind., Ltd.); mobile phase: 0.5 M NaClO₄ /CH₃CN=77/23; flow rate: 0.5 ml/min.; detection wave length: 254 nm;temperature: 40° C.

EXAMPLE 14(R)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

The synthesis was performed in accordance with the procedures as givenin Example 12 except that the hydrogenolysis with 10% palladium/carbonblack in the step G of Example 12 was not incorporated.

A. Synthesis of (R)-2-bromo-1-(3-nitrophenyl)ethanol (Intermediate 25)

To a solution of 769 mg of 2-bromo-1-[3'-nitrophenyl]ethanone and 100 mgof the said asymmetric catalyst [(R)-modification; supplied from TokyoChemical Industry Co., Ltd.] in 20 ml of anhydrous tetrahydrofuran(prepared on each use), 2.16 ml of a 2 M solution of borane/dimethylsulfide complex in tetrahydrofuran (supplied from the firm Aldrich) wereadded dropwise over a period of 5 minutes, whereupon the reaction andthe after-treatments were performed, whereby 768 mg of theabove-identified compound were obtained. Rf=0.72 (ethyl acetate/n-hexaneof 1/1).

Retention time: 9.02 min. Analytical conditions: column: CHIRALCEL AD(supplied from Daicel Chem. Ind., Ltd.); mobile phase:n-hexane/2-propanol (1/1); flow rate: 0.5 ml/min.; detection wavelength: 254 nm; temperature: 35° C.

B. Synthesis of (R)-3-[2-iodo-1-(triethylsilyloxy)ethyl]nitrobenzene(Intermediate 26)

To a solution of 768 mg of Intermediate 25 in 30 ml of acetone, 2.96 gof sodium iodide (supplied from Wako Pure Chemical Ind., Ltd.) wereadded, followed by reaction and after-treatment. 795 mg of the resultingproduct, 408.5 mg of imidazole and 24.4 mg of dimethylaminopyridine weredissolved in 5 ml of dimethylformaide, whereto 452 mg of triethylsilanechloride were added under ice-cooling, followed by reaction andafter-treatment, whereby 994 mg of the above-identified compound wereobtained. Rf=0.43 (ethyl acetate/n-hexane of 1/3).

C. Synthesis of(R)-N,N-[[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-(3-nitrophenyl)ethyl]amine(Intermediate 27)

A solution of 451 mg of Intermediate 26, 330 mg of Intermediate 2 and1.02 ml of Hunig base (supplied from the firm Aldrich) in 2 ml ofdimethylformamide was subjected to reaction and after-treatment, whereby217 mg of the above-identified compound were obtained.

D. Synthesis of(R)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-(3-nitrophenyl)]ethyl]amine(Intermediate 27)

217 mg of the above amine compound were dissolved in 2 ml of methylenechloride and thereto were added 66 μl of triethylamine with subsequentagitation under ice-cooling and further addition of 63 μl of benzylchloroformate (supplied from the firm Aldrich), followed by reaction andafter-treatment, whereby 261 mg of the above-identified compound wereobtained. Rf=0.32 (ethyl acetate/n-hexane of 1/2).

E. Synthesis of(R)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyoxy)-2-(3-aminophenyl)]ethyl]amine

To a solution of 261 mg of the above nitro compound in 5.5 ml ofmethanol which had been purged by argon, 5 mg of platinum oxide(anhydrous, supplied from Wako Pure Chem. Ind., Ltd.) were added toeffect reduction with 1 atm. hydrogen gas, followed by after-treatmentto obtain 236 mg of the above-identified compound.

F. Synthesis of(R)-N-[3-[2-[benzyloxycarbonyl-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(triethylsilyloxy)ethyl]phenyl]methanesulfonamide(Intermediate 28)

To a solution of 236 mg of the above amine compound in 1 ml of pyridine.30 μl of methanesulfonyl chloride were added to cause reaction, followedby after-treatment to obtain 253 mg of the above-identified compound.Rf=0.25 (ethyl acetate/n-hexane of 1/2).

G. Synthesis of(R)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

According to the procedures of the step C in Example 1, the abovemethanesulfonamide compound was processed by adding to 253 mg thereof 5ml of 30% solution of hydrogen bromide in acetic acid to cause reaction,followed by after-treatment to obtain the above-identified compound.

Retention time: 29.3 min. Analytical conditions: column: CHIRALCEL OJ-R(supplied from Daicel Chem. Ind., Ltd.); mobile phase: 0.5 M NaClO₄ /CH₃CN=7/3; flow rate: 0.5 ml/min.; detection wave length: 254 nm;temperature: 30° C.

EXAMPLE 15(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

The reactions and the after-treatments were performed in the same manneras in Example 14, except that an asymmetric catalyst of (S)-modification(supplied from Tokyo Chemical Industry Co., Ltd.) was used.

A. Synthesis of (S)-2-bromo-1-(3-nitrophenyl)ethanol

Retention time: 8.18 min. Analytical conditions: column: CHIRALCEL AD(supplied from Daicel Chem. Ind., Ltd.); mobile phase:n-hexane/ethanol=1/1; flow rate: 0.5 ml/min.; detection wave length: 254nm; temperature: 35° C.

G. Synthesis of(S)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

Retention time: 25.3 min. Analytical conditions: column: CHIRALCEL OJ-R(supplied from Daicel Chem. Ind., Ltd.); mobile phase: 0.5 M NaClO₄ /CH₃CN=7/3; flow rate: 0.5 ml/min.; detection wave length: 254 nm;temperature: 30° C.

EXAMPLE 16(±)-N-methyl-3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]benzenesulfonamidehydrochloride

A. Synthesis of N-methyl-3-acetylbenzenesulfonamide

To a solution of 2 g of 3-acetylbenzenesulfonyl fluoride (supplied fromthe firm Acros) in 20 ml of pyridine, 2,02 ml of 40%methylamine/methanol (supplied from Wako Pure Chem. Ind. Co., Ltd.) wereadded at room temperature and the mixture was agitated for 2 hours.There were replenished 2.02 ml of 40% methylamine/methanol and theagitation was continued for further 40 minutes. Thereto were added 5 Nhydrochloric acid and about 40 ml of water to terminate the reaction (pH4) and the product was extracted with ethyl acetate. The organic layerwas separated and dried and the solvent was distilled off under areduced pressure, whereby 996 mg of the above-identified compound wereobtained. Rf=0.64 (methanol/chloroform of 1/10).

B. Synthesis of N-methyl-3-(2-bromoacetyl)benzenesulfonamide(Intermediate 29)

To a solution of 990 mg of the above-obtained compound in 15.8 ml of1,4-dioxane, 769 mg of bromine were added and the mixture was stirredfor 1 hour at 60° C. The mixture was concentrated under a reducedpressure, followed by addition of 18 ml of water to the residue,whereupon the resulting mixture was agitated vigorously underice-cooling. The deposited precipitate was triturated and separated byfiltration and was washed with water. The separated product was driedunder a reduced pressure at room temperature, whereby 1.18 g of theabove-identified compound were obtained. Rf=0.63 (methanol/chloroform of1/10).

C. Synthesis of(±)-N-methyl-3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]benzenesulfonamidehydrochloride

According to the procedures described in the step D of Example 1, 0.59 gof the above Intermediate 29, 0.59 g of HBr-addition salt ofIntermediate 2, 0.39 g of sodium borohydride and 1 ml of ethanolaminewere brought into reaction, followed by after-treatment, whereby 227.8mg of the above-identified compound were obtained,wherein the procedureswere modified such that 0.56 ml (2 eq.) of triethylamine was used as thebasic catalyst and the purification was effected by a columnchromatography (methanol/ethyl acetate of 1/5), with subsequent PTLC(methanol/ethyl acetate of 1/5). Rf=0.28 (methanol/ethyl acetate of1/5).

EXAMPLE 17(±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]formamidehydrochloride

A. Synthesis of 1-(3-formylaminophenyl)ethanone

To a solution of 2 g of 1-(3-aminophenyl)ethanone (supplied from TokyoChemical Industry Co., Ltd.) in 15 ml of dimethylformamide, a mixture of15 ml of formic acid and 5 ml of acetic anhydride was added and themixture was agitated for 2.5 hours. Then, the agitation was continuedfor further 15 hours at room temperature and thereto was added a mixtureof 3 ml of formic acid and 1 ml of acetic anhydride and agitation wascontinued for further 8 hours at room temperature. To this mixture, 150ml of water and 150 ml of ethyl acetate were added to effect extraction.The organic layer was rinsed with water twice and dried, whereupon thesolvent was distilled off under a reduced pressure to obtain 1.69 g ofthe above-identified compound. Rf=0.65 (methanol/chloroform of 1/10).

B. Synthesis of(±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]formamidehydrochloride

To a solution of 1.6 g of the above 1-(3-formylaminophenyl)ethanone in33.4 ml of 1,4-dioxane, 1.63 g of bromine were added and the mixture wasagitated for 1 hour at 60° C. The mixture was concentrated under areduced pressure, 40 ml of water were added to the resulting residue andthe mixture was agitated vigorously under ice-cooling. To this mixturewas added ethyl acetate to effect extraction and the organic layer wasdried, before the solvent was distilled off under a reduced pressure. Tothe resulting residue, chloroform and water were added and the depositedprecipitate was separated by filtration. By distilling off the solventfrom the filtrate under a reduced pressure, 975 mg of a mixturecontaining 2-bromo-1-(3-formylaminophenyl)ethanone were obtained.

According to the procedures as described in the step D of Example 1, 300mg of the mixture containing the above bromo-product, 363 mg ofHBr-addition salt of Intermediate 2, 239 mg of sodium borohydride and0.6 ml of ethanolamine were brought into reaction,followed byafter-treatment, whereby 73 mg of the above-identified compound wereobtained, wherein, however, a modification was incorporated in such amanner that 0.34 ml (2 eq.) of triethylamine was used as a basiccatalyst and the purification was effected by a PTLC (methanol/ethylacetate of 1/3) with subsequent conversion into hydrochloride salt,followed by removal of impurities by depositing them from methanol/ethylacetate and filtering them off. Rf=0.26 (methanol/ethyl acetate of 1/3).

EXAMPLE 18(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxy-3-nitrophenyl)]ethanolhydrochloride

A. Synthesis of(±)-[2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-nitro-4-(benzyloxy)phenyl]ethanol

According to the procedures described in the step D of Example 1, asolution of 0.52 g (70% purity) of2-bromo-1-[3-nitro-4-(benzyloxy)phenyl]ethanone [prepared by the methodreported by Carl Kaiser et al in J. Med. Chem., 17, 49-57(1974)] in amixture of 409 μl of triethylamine and 6.4 ml of anhydrous acetonitrileand a solution of 287 mg of sodium borohydride in 13 ml of absoluteethanol were added successively to a solution of 435 mg of HBr-additionsalt of Intermediate 2 in a mixed solvent composed of 25.5 ml ofanhydrous acetonitrile and 20 ml of anhydrous dimethylformamide,followed by reaction and after-treatment, whereby 61.8 mg of theabove-identified compound were obtained. Rf=0.24 (methanol/chloroform of1/10).

B. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxy-3-nitrophenyl)ethanolhydrochloride

To a solution of 127.6 mg of the compound of the above step A in 10 mlof dichloromethane, 0.69 ml of 1 M solution of boron tribromide indichloromethane (supplied from the firm Aldrich) was added dropwise overa period of 2 minutes under cooling with dry ice/acetone coolant. Themixture was agitated as such for one hour and, then, the agitation wascontinued for further 5 minutes under ice-cooling. The reaction wasterminated by adding 10 ml of methanol to the reaction mixture and theproduct was extracted therefrom with ethyl acetate after adjusting thereaction mixture at pH of 8.7 using saturated aqueous sodium bicarbonatesolution. The organic layer was rinsed with saturated aqueous sodiumchloride solution and dried, whereupon the solvent was distilled offunder a reduced pressure. The resulting residue was triturated in ethylacetate and the mixture was filtered to obtain 87.6 mg of free baseproduct of the above-identified compound. This was converted intohydrochloride salt which is the above-identified compound by using 0.1 NHCl/ethanol (93.0 mg). Rf=0.33 (methanol/chloroform of 1/10).

EXAMPLE 19(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-amino-4-hydroxyphenyl)ethanol.2HCl

15 mg of the compound of Example 18 were dissolved in a mixed solventcomposed of 1 ml of methanol and 1 ml of tetrahydrofuran in accordancewith the procedures described in the step E of Example 12 and theretowere added 1.1 mg of platinum oxide (anhydrous, supplied from Wako PureChem. Co.) under ice-cooling, followed by reaction and after-treatment,whereby 10.2 mg of the above-identified compound were obtained. Rf=0.15(methanol/ethyl acetate of 1/3).

EXAMPLE 20(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]ureahydrochloride

According to the procedures described in the step D of Example 1, asolution of 0.54 g of 2-bromo-1-[4-(benzyloxy)-3-ureidphenyl]ethanone[prepared by the method reported by Carl Kaiser et al in J. Med. Chem.,17, 49-57 (1974)] in a mixture of 409 μl of triethylamine and 6.4 ml ofanhydrous acetonitrile and a solution of 287 mg of sodium borohydride in13 ml of absolute ethanol were added successively to a solution of 435mg of HBr-addition salt of Intermediate 2 in a mixed solvent composed of26 ml of anhydrous acetonitrile and 10 ml of anhydrousdimethylformamide, followed by reaction and after-treatment, whereby59.3 mg of the above-identified compound were obtained. Rf=0.15(methanol/chloroform of 1/10).

EXAMPLE 21 Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]ureahydrochloride

According to the procedures as given in Example 2, the compound ofExample 20 (in a solution of 40 mg of the compound in 5.3 ml ofmethanol) was subjected to a hydrogenolysis using 10% palladium/carbonblack (25 mg), whereby the above-identified compound (29.8 mg) wasobtained. Rf=0.08 (methanol/chloroform of 1/10).

EXAMPLE 22 Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]formamidehydrochloride

According to the procedures described in the step D of Example 1, asolution of 0.52 g of2-bromo-1-[3-(formylamino)-4-(benzyloxy)phenyl]ethanone [prepared by themethod reported by Carl Kaiser et al in J. Med. Chem., 17, 49-57 (1974)]in a mixture of 409 μl of triethylamine and 10 ml of anhydrousacetonitrile and a solution of 287 mg of sodium borohydride in 13 ml ofabsolute ethanol were added successively to a solution of 435 mg ofHBr-addition salt of Intermediate 2 in a mixed solvent composed of 22 mlof anhydrous acetonitrile and 6 ml of anhydrous dimethylformamide,followed by reaction and after-treatment, whereby 57.0 mg of theabove-identified compound were obtained. Rf=0.18 (methanol/chloroform of1/10).

EXAMPLE 23 Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]formamidehydrochloride

According to the procedures as given in Example 2, the compound ofExample 22 (in a solution of 40 mg of the compound in 5.8 ml ofmethanol) was subjected to a hydrogenolysis using 10% palladium/carbonblack (27 mg), whereby the above-identified compound (28.1 mg) wasobtained. Rf=0.08 (methanol/chloroform of 1/10).

EXAMPLE 24 Synthesis of(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N,N-dimethylsulfamidehydrochloride

According to the procedures described in the step D of Example 1, asolution of 0.64 g of2-bromo-1-[4-(benzyloxy)-3-(dimethylsulfamoylamino)phenyl]ethanone[preparedby the method reported by Carl Kaiser et al in J. Med. Chem., 17, 49-57(1974)] in a mixture of 410 μl of triethylamine and 6.5 ml of anhydrousacetonitrile and a solution of 287 mg of sodium borohydride in 15 ml ofabsolute ethanol were added successively to a solution of 435 mg ofHBr-addition salt of Intermediate 2 in a mixed solvent composed of 26 mlof anhydrous acetonitrile and 10 ml of anhydrous dimethylformamide,followed by reaction and after-treatment, whereby 70.5 mg of theabove-identified compound were obtained. Rf=0.17 (methanol/chloroform of1/10).

EXAMPLE 25 Synthesis of(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

According to the procedures as given in Example 2, the compound ofExample 24 (in a solution of 40 mg of the compound in 5.1 ml ofmethanol) was subjected to a hydrogenolysis using 10% palladium/carbonblack (24 mg), whereby the above-identified compound (38.3 mg) wasobtained. Rf=0.38 (methanol/ethyl acetate of 1/3).

EXAMPLE 26(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-(benzyloxy)phenyl]ethanol.2HCl

According to the method reported by Carl Kaiser et al in J. Med. Chem.,17, 49-57 (1974), a solution of 500 mg of the compound of Example 22 in1 ml of tetrahydrofuran was added dropwise to a suspension of 50 mg oflithium aluminum hydride in 2 ml of tetrahydrofuran to cause reaction,followed by after-treatment, whereby 381 mg of the above-identifiedcompound were obtained. Rf=0.13 (methanol/chloroform of 1/10).

EXAMPLE 27(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-hydroxyphenyl]ethanol.2HCl

According to the procedures as given in Example 2, the compound ofExample 26 (in a solution of 200 mg of the compound in 25 ml ofmethanol) was subjected to a hydrogenolysis using 10% palladium/carbonblack (100 mg), whereby the above-identified compound (153 mg) wasobtained. Rf=0.09 (methanol/chloroform of 1/10).

EXAMPLE 28(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-fluorophenyl)ethanolhydrochloride

A. Synthesis of (±)-2-fluorostyrene oxide (Intermediate 30)

To a solution of 5.00 g of 2-fluorostyrene (supplied from the firmAldrich) in 200 ml of methylene chloride, 17.7 g of metachloroperbenzoicacid (supplied from Kanto Chem. Co. Inc.) and 18.6 g of disodiumphosphate were added under ice-cooling and the mixture was agitated atroom temperature for 20 hours. The mixture was cooled with ice and thethereby deposited crystals were removed by twice filtrations and thefiltered cake was washed with aqueous sodium thiosulfate solution (180ml), whereupon the organic phase was dried and the solvent was distilledoff under a reduced pressure, followed by purification by a columnchromatography (ethyl acetate/n-hexane of 1/19), whereby 0.38 g of theabove-identified compound was obtained. Rf=0.57 (ethyl acetate/n-hexaneof 1/5).

B. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-fluorophenyl)ethanolhydrochloride

Under argon atmosphere, 1.6 ml of dimethyl sulfoxide and 1.06 ml ofN,O-bis(trimethylsilyl)acetamide (25% solution in acetonitrile, suppliedfrom Tokyo Chemical Industry Co., Ltd.) were added to 452.6 mg ofIntermediate 2 and the resulting mixture was agitated at roomtemperature for 30 minutes. Thereto were then added 290 mg ofIntermediate 30 and the agitation was continued at 70° C. for 70 hours.

The reaction mixture was cooled down to room temperature and 2 ml of 6 Nhydrochloric acid were added thereto and the mixture was agitated for 5minutes, whereupon the resulting mixture was made basic using 5 Naqueous sodium hydroxide. Then, the mixture was extracted with ethylacetate, whereupon the organic phase was dried and the solvent wasdistilled off under a reduced pressure, followed by purification by acolumn chromatography (chloroform-methanol/chloroform of 3/100-7/100) toobtain a free amine product of the above-identified compound. Rf=0.20(methanol/chloroform of 1/9). Using 0.1 N hydrogen chloride/ethanol, 268mg of the above-identified compound were obtained.

EXAMPLE 29(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxyphenyl)ethanolhydrochloride

A. Synthesis of 2-bromo-1-(4-benzyloxy)phenylethanone (Intermediate 31)

Under argon atmosphere, 7.4 g of copper(II) bromide were suspended in100 ml of ethyl acetate and thereto was added a solution of 5 g of1-(4-benzyloxy)-phenylethanone (supplied from the firm Transworld) in100 ml of chloroform with agitation while heating under reflux. Afteragitation for 5.5 hours, the mixture was cooled down to 62° C. and wasdiluted with 100 ml of chloroform, followed by filtration of thesuspension and evaporation under a reduced pressure. The resultingresidue was suspended in isopropyl alcohol and precipitate was removedby filtration. followed by rinsing with cold isopropyl alcohol anddrying, whereby 4.52 g of the above-identified compound were obtained aspale yellow crystals.

B. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[4-(benzyloxy)phenyl]ethanol(Intermediate 32)

400 mg of Intermediate 31 and 534 mg of Intermediate 2 were subjected toreaction and after-treatment in accordance with the procedures of thestep D of Example 1, whereby 120 mg of the above-identified compoundwere obtained. Here, however, the crude product was purified by a columnchromatography (ethyl acetate/methanol of 8/1).

C. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxyoxyphenyl)ethanol

120 mg of Intermediate 32 were dissolved in 15 ml of dimethylformamide,whereto were added 100 μl of acetic acid and, then, 120 mg of 10%palladium/carbon black rinsed with 2 ml of dimethylformamide, whereuponthe mixture was subjected to a hydrogenolysis under 1 atm for 50minutes. After-treatments were effected in accordance with theprocedures of Example 2, whereby 88 mg of the above-identified compoundwere obtained. Rf=0.31 (methanol/ethyl acetate of 1/3).

EXAMPLE 30(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-hydroxyphenyl)ethanolhydrochloride

A. Synthesis of 2-bromo-1-(2-benzyloxy)phenylethanone

Under argon atmosphere, 14.6 g of copper (II) bromide were suspended in175 ml of ethyl acetate and thereto was added a solution of 6.35 g of1-(4-benzyloxy)phenylethanone (supplied from the firm Transworld) in 175ml of chloroform with agitation while heating under reflux. Byafter-treatment in accordance with the procedures of the step A ofExample 29, a fraction containing the above-identified compound (9.32 g)was obtained, which was served for the subsequent reaction as suchwithout further treatment.

B. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[2-(benzyloxy)phenyl]ethanol(Intermediate 33)

442 mg of the above-obtained compound and 400 mg of Intermediate 2 weresubjected to reaction and after-treatment in accordance with theprocedures of the step D of Example 1, whereby 31.9 mg of theabove-identified compound were obtained. Here, however, the crudeproduct was purified by a column chromatography (methanol/chloroform of1/20).

D. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-hydroxyphenyl)ethanolacetic acid addition salt

31.9 mg of Intermediate 33 were dissolved in 4.7 ml of methanol andthereto were added 4 μl of acetic acid and the mixture was subjected toa hydrogenolysis under 1 atm hydrogen gas using 22.3 mg of 10%palladium/carbon black (room temperature, 5 hours). The catalyst wasfiltered off on celite and was washed with chloroform and methanol. Thefiltrate and the washed liquor were brought together, from which thesolvent was distilled off under a reduced pressure, whereby 18.5 mg ofthe above-identified compound were obtained as a powdery product.Rf=0.13 (methanol/chloroform of 1/10).

EXAMPLE 31 (±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanolhydrochloride

To a solution of 140 mg of HBr addition salt of Intermediate 2 and 110μl of triethylamine in 5 ml of methanol, 92.0 mg of phenylglyoxal wereadded and the mixture was heated on a water bath for 4 minutes. Aftercooling, 120 mg of sodium borohydride were added thereto in two portionsat an interval of 10 minutes and the mixture was agitated at roomtemperature for 20 hours. The solvent was distilled off under a reducedpressure and thereto were added ethyl acetate and water to cause liquidseparation, whereupon the organic solvent was dried and evaporated offunder a reduced pressure. The resulting residue was purified by a columnchromatography (methanol/chloroform of 1/25), whereby 116.3 mg of theabove-identified compound were obtained. By recrystallization fromethanol,93.8 mg were obtained as hydrochloric acid addition salt.Rf=0.34 (methanol/chloroform of 1/10).

EXAMPLE 32 (R)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanolhydrochloride

To 200 mg of Intermediate 2, 0.5 ml of dimethylsulfoxide and 102 μl of(R)-(+)-styrene oxide (supplied from the firm Aldrich) were added andthe resulting mixture was agitated at 70° C. for 70 hours. The mixturewas made basic with addition of water and sodium hydrogen carbonate andwas then subjected to extraction with ethyl acetate, followed by dryingof the organic layer, whereupon the solvent was distilled off under areduced pressure and the resulting residue was purified by a columnchromatography (methanol/chloroform of 1/20) to obtain 93.4 mg of theabove-identified compound. Rf=0.34 (methanol/chloroform of 1/10).

The optical purity was found to be such that it is constituted of nearly100% of (R)-modification after high performance liquid chromatographyusing CHIRALCEL OD-R (4.6 mm φ×25 cm, of Daicel Chem. Ind.). Theanalysis was carried out with a mobile phase of 0.5 M NaClO₄ /CH₃ CN of1/1, a flow rate of 0.5 ml/min., a detection wave length of 254 nm, acolumn temperature of 25° C. with retention time of 33.2 min. for(R)-modification and 32.4 min. for (S)-modification respectively. Usingan ethanolic hydrogen chloride solution, 70 mg of hydrochloric acidaddition salt were obtained.

EXAMPLE 33 (S)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanolhydrochloride

To 70.4 mg of Intermediate 2, 0.3 ml of dimethyl sulfoxide and 36 μl of(S)-(-)-styrene oxide (supplied from the firm Aldrich) were added andthe resulting mixture was agitated at 70° C. for 70 hours. The mixturewas made basic with addition of water and sodium hydrogen carbonate andwas then subjected to extraction with ethyl acetate, followed by dryingof the organic layer, whereupon the solvent was distilled off under areduced pressure and the resulting residue was purified by a PTLC(chloroform/methanol of 10/1) to obtain 22.4 mg of the above-identifiedcompound. Rf=0.34 (methanol/chloroform of 1/10). The optical purity wasfound, after high performance liquid chromatography as in Example 32with the analysis under the same condition, to be such that it isconstituted of nearly 100% of (S)-modification and the retention timewas found to be 32.4 min. By using an ethanolic hydrogen chloridesolution, 15 mg of hydrochloric acid addition salt were obtained.

EXAMPLE 34(±)-2-[N-[2-(dibenzofuran-2-yloxy)ethyl]amino]-1-phenylethanolhydrochloride

To a solution of 105 mg of HBr-addition salt of Intermediate 2 and 110μl of triethylamine in 5 ml of methanol, 69 mg of phenylglyoxal wereadded, followed by procedures in accordance with those of the synthesismethod in Example 31, whereby 63.6 mg of the above-identified compoundwere obtained. Rf=0.48 (methanol/chloroform of 1/10). Using an ethanolicsolution of hydrogen chloride, 40 mg of hydrochloride salt wereobtained.

EXAMPLE 35(R,R)-2-[N-[1-(9H-carbazol-2-yloxy)propan-2-yl]amino]-1-phenylmethanolhydrochloride

To 597 mg of 2-(N-tert-butoxycarbonylamino-1-propyloxy)-9H-carbazolesynthesized according to the procedures of Example 11, 10 ml of 30%solution of hydrogen bromide in acetic acid were added and the reactionand the after-treatments were carried out in accordance with theprocedures of the synthesis of Example 32, whereby 258 mg of theabove-identified compound were obtained. Rf=0.47 (methanol/chloroform of1/9). The optical purity was found by an analysis performed under thesame condition as in Example 32 except that it was carried out using ahigh performance liquid chromatography at 30° C. to be such that theproduct was constituted of nearly 100% in the form of(R,R)-modification. The retention time was 27.3 minutes. The product wasconverted into hydrochloric acid addition salt by using 6 N hydrochloricacid (280 mg).

EXAMPLE 36(±)-2-[N-[2-[(9H-3-aminocarbazol)-2-yloxy]ethyl]amino]-1-phenylethanol.2HCl

A. Synthesis of N-[2-(9H-carbazol-2-yloxy)ethyl]acetamide (Intermediate34)

To a solution of 1 g of Intermediate 2 and 0.93 ml of triethylamine(supplied from Wako Pure Chemical Ind., Ltd.) in 5 ml ofdichloromethane, solution of 0.4 ml of acetyl chloride (supplied fromWako Pure Chemical Ind.) in 2 ml of dichloromethane were added underice-cooling and agitation. The mixture was agitated for 2.5 hours underice-cooling and, then, warmed to room temperature. Thereto were addedethyl acetate and water and the organic layer was separated, which waswashed with aqueous saturated aqueous sodium chloride solution anddried, whereupon the solvent was distilled off under a reduced pressure.The resulting product was dried at room temperature under a reducedpressure, whereby 1.16 g of the above-identified compound were obtained.Rf=0.47 (methanol/chloroform of 1/9).

B. Synthesis of N-[2-[(9H-3-nitrocarbazol)-2-yloxy]ethyl]acetamide(Intermediate 35)

To a solution of 500 mg of Intermediate 34 in 20 ml of acetic acid, 0.4ml of 20% nitric acid at 60° C. under agitation. After 1 minute, 20 mlof ice water were added thereto and the mixture was agitated, whereuponwater was further added thereto, followed by extraction with ethylacetate. Organic layer was washed with water, adjusted at pH 8 with 5 Naqueous sodium hydroxide solution and washed with saturated aqueoussodium chloride solution. After drying, the solvent was distilled offunder a reduced pressure and the resulting residue was purified by acolumn chromatography (methanol/chloroform of 1/50), whereby 271.2 mg ofthe above-identified compound were obtained. Rf 0.50 (twice developmentswith methanol/chloroform of 1/9).

C. Synthesis of N-2-[(9H-3-nitrocarbazol)-2-yloxy]ethyl]amine(Intermediate 36)

100 mg of Intermediate 35 were suspended in 2.5 N hydrochloric acid andthe mixture was agitated at room temperature for 10 days and, then,agitation was further continued at 100° C. for 4 hours. To this mixturewas added ethyl acetate and pH thereof was adjusted at 10 using 5 Naqueous sodium hydroxide to perform extraction. After drying, thesolvent was distilled off under a reduced pressure, whereby 71.2 mg ofthe above-identified compound were obtained. Rf=0.11 (thricedevelopments with methanol/chloroform of 1/10).

D. Synthesis of(±)-2-[N-[2-[9H-3-nitrocarbazol)-2-yloxy]ethyl]amino]-1-phenylethanolhydrochloride (Intermediate 37)

71.2 mg of Intermediate 36, 52,8 mg of phenylglyoxal (supplied fromTokyo Chemical Industry Co., Ltd.) and 54.8 μl of triethylamine weredissolved in 5 ml of methanol and the mixture was agitated at 70° C. for4 minutes. The mixture was then cooled with ice and thereto were added79 mg of sodium borohydride under agitation. Agitation was continued forfurther 21 hours, while the temperature was allowed to rise gradually toroom temperature. Ethyl acetate and water were added thereto and themixture was agitated for 15 minutes, whereupon the organic layer wasseparated and dried and the solvent was distilled off under a reducedpressure. The resulting residue (112.1 mg) was purified by a columnchromatography (methanol/chloroform of 1/25), whereby 17.1 mg of theabove-identified compound were obtained. Rf=0.34 (methanol/chloroform of1/10).

E. Synthesis of(±)-2-[N-[2-[(9H-3-aminocarbazol)-2-yloxy]ethyl]amino]-1-phenylethanol.2HCl

To a solution of 71.8 mg of the compound of Intermediate 37 in 3.7 ml ofmethanol, 0.16 ml of concentrate hydrochloric acid and 68.6 mg of ironpowder (supplied from Kanto Chemical Co., Inc.) were added,successively, and the mixture was agitated at room temperature for 3.5hours and,then,agitation was continued at 40° C. for additional 5minutes. The mixture was adjusted at pH 9 using water and 5 N aqueoussodium hydroxide solution, followed by extraction with ethyl acetate anddrying, whereupon the solvent was distilled off under a reducedpressure. To the resulting residue were added 4 ml of 0.1 N hydrogenchloride/ethanol and the solvent was distilled off under a reducedpressure, whereupon recrystallization from ethanol/ethyl acetate wasincorporated. The crystals were isolated by filtration and were washedwith ethyl acetate and diethyl ether, successively, with subsequentdrying under a reduced pressure, whereby 29 mg of the above-identifiedcompound were obtained. Rf=0.14 (free compound, methanol/chloroform of1/10).

EXAMPLE 37(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamidehydrochloride

A. Synthesis of 3-(2-benzyloxycarbonylaminoethoxy)dibenzothiophene(Intermediate 38)

To a solution of 370.6 mg of 3-hydroxydibenzothiophene [prepared by themethod reported by H. Kudo in J. Heterocycl. Chem., 22 (1), 215-218(1985)] and 768 mg of potassium carbonate in 4 ml of dimethylformamide,720 mg of Intermediate 0 were added and the mixture was heated at 60° C.for 30 hours. Thereto were added ethyl acetate and water to effectextraction, whereupon the organic layer was dried and the solvent wasdistilled off under a reduced pressure to thereby obtain 637 mg of theabove-identified compound after purification by a column chromatography(mathanol/chloroform of 1/100). Rf=0.17 (ethyl acetate/n-hexane of 1/5).

B. Synthesis of 2-(dibenzothiophen-3-yloxy)ethylamine (Intermediate 39)

To 637 mg of Intermediate 38, 12 ml of 30% solution of hydrogen bromidein acetic acid were added and the mixture was agitated at roomtemperature for 2.5 hours. Thereto was added diethyl ether underice-cooling and the thereby deposited precipitate was filtered off.After adjusting the pH of the remainder to 10 by adding water and NaOH,extraction with ethyl acetate was incorporated and the organic layer wasdried, before the solvent was distilled off under a reduced pressure,whereby 334.2 mg of the above-identified compound were obtained. Rf=0.10(methanol/chloroform of 1/10).

C. Synthesis of(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamidehydrochloride

To a solution of 334.2 mg of Intermediate 39 in 14 ml of anhydrousacetonitrile, a solution of 980 mg of Intermediate 3 (70% purity) in 7ml of anhydrous acetonitrile and 210 μl of triethylamine were addedunder argon atmosphere at 0° C., whereupon the reaction mixture wasremoved from the ice bath and was agitated for 83 minutes. Thereto wasthen added a solution of 270 mg of sodium borohyride in 14 ml ofabsolute ethanol at room temperature. After agitation for 6.5 hours, thereaction was terminated using 1.0 N hydrochloric acid (pH 4) and theretowas added 0.7 g of ethanolamine. After agitation for 10 minutes, themixture was diluted with ethyl acetate, organic layer was rinsed withsaturated aqueous sodium chloride solution and dried and the solvent wasdistilled off under a reduced pressure, whereby 1.09 g of crude productwere obtained. This was purified by a column chromatography(methanol/chloroform of 3/100), whereby 240.6 mg of free amine productof the above-identified compound were obtained. Rf=0.38(methanol/chloroform of 1/10). To a part (46 mg) of the so-obtainedproduct, 1.1 equivalent amount of 0.1 N hydrogenchloride/ethanol wereadded to convert it into hydrochloride salt (the above-identifiedcompound), whereupon the solvent was distilled off under a reducedpressure. To the resulting residue, diethyl ether was added and thethereby deposited precipitate was filtered off, whereupon the filtratewas rinsed with diethyl ether and dried under a reduced pressure at 50°C. whereby 48.5 mg of the above-identified compound were obtained.

EXAMPLE 38(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

43 mg of the compound of Example 37 were subjected to a hydrogenolysisunder 1 atm hydrogen gas using 30 mg of 10% palladium/carbon black(supplied from the firm Merck) and 5 ml of methanol. The catalyst wasfiltered off and washed with chloroform, methanol and hot methanol,successively. The filtrate and the washed liquor were brought together,from which the solvent was distilled off under a reduced pressure,whereby 32.5 mg of the above-identified compound were obtained as awhite powdery product. Rf=0.08 (methanol/chloroform of 1/10).

EXAMPLE 39(±)-N'-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamidehydrochloride

A. Synthesis of2-bromo-1-[4-benzyloxy-3-[(dimethylsulfamoyl)amino]phenyl]ethanone(Intermediate 40)

In the same manner as in the case of Intermediate 3, the above wasprepared from 4-hydroxyacetophenone (supplied from Tokyo ChemicalIndustry Co., Ltd.) in four process steps [by the method reported by A.A. Larsen et al in J. Med. Chem., 10, 462-472 (1967)], wherein however,bromination was effected in the same manner as the procedures given inthe step A of Example 29. Rf=0.37 (chloroform).

B. Synthesis of(±)-N'-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamidehydrochloride

To a solution of 462 mg of Intermediate 39 in 20 ml of anhydrousacetonitrile, a solution of 470 mg of Intermediate 40 in 10 ml ofanhydrous acetonitrile was added under argon atmosphere at 0° C.,whereupon the reaction mixture was removed from the ice bath and wasagitated for 110 minutes. Thereto was then added a solution of 215 mg ofsodium borohydride in 20 ml of absolute ethanol at room temperature.After agitation for 70 minutes, the reaction was terminated using 1 Nhydrochloric acid (pH 4) and the thereto was added 0.54 g ofethanolamine. After agitation for 10 minutes, the mixture was dilutedwith ethyl acetate, organic layer was rinsed with saturated aqueoussodium chloride solution and dried, whereupon it was evaporated under areduced pressure, whereby a crude product was obtained. This waspurified by a column chromatography (methanol/chloroform of 3/100),whereby 200.2 mg of free amine product of the above-identified compoundwere obtained. Rf=0.37 (methanol/chloroform of 1/10). The procedures ofadding thereto 1.1 equivalent amount of 0.1 N hydrogen chloride/ethanolto convert it into hydrochloride salt (the above-identified compound),distilling off of the solvent under a reduced pressure, adding to theresulting residue diethyl ether and filtering off the thereby depositedprecipitate were repeated twice, followed by drying under a reducedpressure, whereby 210.8 mg of the above-identified compound wereobtained.

EXAMPLE 40(±)-N'-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

210.8 mg of the compound of Example 39 were subjected to ahydrogenolysis under 1 atm hydrogen gas using 107 mg of 10%palladium/carbon black and 22.5 ml of methanol. The catalyst wasfiltered off and washed with hot methanol. The filtrate and the washedliquor were brought together, from which the solvent was distilled offunder a reduced pressure, whereby 137.9 mg of the above-identifiedcompound were obtained. Rf=0.26 (methanol/chloroform of 1/10).

EXAMPLE 41(±)-N-[3-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

To a solution of 462 mg of Intermediate 39 in 20 ml of anhydrousacetonitrile, a solution of 320.2 mg of Intermediate 14 in 10 ml ofanhydrous acetonitrile was added under argon atmosphere at 0° C.,whereupon the reaction mixture was removed from the ice bath and wasagitated for 115 minutes. To this mixture was then added a solution of215 mg of sodium borohydride in 20 ml of absolute ethanol at roomtemperature. After agitation for 75 minutes, the reaction was terminatedusing 1 N hydrochloric acid (pH 4) and thereto was added 0.54 g ofethanolamine. After agitation for 10 minutes, the mixture was dilutedwith ethyl acetate, organic layer was rinsed with saturated aqueoussodium chloride solution and dried, whereupon it was evaporated under areduced pressure. This was purified by a column chromatography (elutionby methanol/ethyl acetate of 1/7), whereby 251.3 mg of fractionscontaining the free amine product of the above-identified compound wereobtained. This was further purified by a PTLC (elution withmethanol/ethyl acetate of 1/7), whereby 134.7 mg of free amine productof the above-identified compound were obtained. Rf=0.50 (methanol/ethylacetate of 1/7). To this, 1.1 equivalent amount of 0.1 N hydrogenchloride/ethanol were added to convert it into hydrochloride salt (theabove-identified compound), which was washed with ethanol, ethyl acetateand diethyl ether, successively, with subsequent drying under a reducedpressure, whereby 93.9 mg of the above-identified compound wereobtained.

EXAMPLE 42(±)-N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide

A. Synthesis of(±)-N-[5-(2-bromo-1-hydroxyethyl)-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 41)

To a solution of 15.1 g Intermediate 40 in 197 ml of anhydroustetrahydrofuran under ice-cooling, a solution of 61.9 ml of 1 Mborane/tetrahydrfuran complex in tetrahydrofuran (supplied from the firmAldrich) were added all at once and the mixture was agitated at thistemperature for 75 minutes. The mixture was then diluted with 500 ml ofethyl acetate and thereto was added saturated aqueous ammonium chloridesolution in small portions to wash the organic layer twice. The organiclayer was separated and was washed with saturated aqueous sodiumchloride solution and dried over anhydrous sodium sulfate, whereupon thesolvent was distilled off under a reduced pressure. The residue wasfurther dried under a reduced pressure overnight using a vacuum pump,whereby 14.91 g of the above-identified compound were obtained.Rf=0.27(ethyl acetate/n-hexane of 1/2).

B. Synthesis of(±)-N-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 42)

To a solution of 14.9 g of Intermediate 41 in 212.9 ml of acetone, 58.09g of sodium iodide were added and the mixture was heated under refluxfor 105 minutes. The mixture was then cooled down to room temperatureand was filtered, before the solvent was distilled off under a reducedpressure. The resulting residue was subjected to a phase partitionbetween 214 ml of dichloromethane and 240 ml of water and the organiclayer was washed twice with 23.5% by weight aqueous sodium hydrogensulfide solution and, then, with saturated aqueous sodium chloridesolution, before it was dried and the solvent was distilled off under areduced pressure. This was further dried under a reduced pressure fortwo hours by a vacuum pump, whereby 15.51 g of brown tar-like product(iodo-isomer) were obtained. This was dissolved in 75.6 ml ofdimethylformamide and thereto were added 6.1 g of imidazole and 346 mgof 4-dimethylaminopyridine, followed by a further addition of 5.83 ml ofchlorotriethylsilane. After agitation for 35 minutes, the mixture wasdiluted with 250 ml of ethyl acetate and 100 ml of n-heptane and, then,washed with water (125 ml), with a saturated copper sulfate solution(twice, 125 ml), with water (125 ml) and, finally, with a saturatedaqueous sodium chloride solution (125 ml), successively, followed bydrying, whereupon the solvent was distilled off under a reducedpressure. The resulting residue was purified by a silica gel columnchromatography and the target compound was obtained (15.41 g) fromn-hexane-eluted fractions as a slightly brownish solid. Rf=0.86 (ethylacetate/n-hexane of 1/1).

C. Synthesis of(±)-N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 43)

A solution of 150 mg of Intermediate 42, 71,6 mg of Intermediate 5 and0.44 ml of Hunig Base (supplied from the firm Aldrich) in 0.5 ml ofdimethylacetamide was agitated at 60° C. for 12 hours. To the reactionmixture, 40 ml of ethyl acetate and 40 ml of water were added to effectextraction and the aqueous phase was further extracted with ethylacetate three times. The united organic phase was dried and the solventwas distilled off under a reduced pressure. The resulting residue waspurified by a column chromatography(chloroform--methanol/chloroform=1/49), whereby 173 mg of theabove-identified compound were obtained. Rf=0.74 (methanol/chloroform of1/10).

D. Synthesis of(±)-N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide

To a solution of 60.1 mg of Intermediate 43 in 2.9 ml of anhydroustetrahydrofuran, 36.8 μl of acetic acid and 574 μl of 1 M solution oftetrabutyl ammonium fluoride in tetrahydrofuran were added and themixture was agitated at room temperature for 1 hour. The reactionmixture was diluted with ethyl acetate and was washed with saturatedaqueous sodium bicarbonate solution and then with saturated aqueoussodium chloride solution, followed by drying, whereupon the solvent wasdistilled off under a reduced pressure. The resulting residue waspurified by a silica gel chromatography,whereupon the above-identifiedcompound (50.0 mg) was obtained from eluted fractions withmethanol/chloroform (7/100). Rf=0.39 (methanol/chloroform of 1/10).

EXAMPLE 43(±)-N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

The compound of Example 42 was dissolved in 5.9 ml of methanol andthereto were added 0.92 ml of 0.1 N hydrogen chloride/ethanol and 27.6mg of 10% palladium/carbon black and the mixture was agitated under 1atm hydrogen gas for 2.5 hours. The catalyst was filtered and washedwith hot methanol, whereupon the solvent was distilled off under areduced pressure. The residue was triturated with diethyl ether and wascollect by filtration. By drying at 50° C. under a reduced pressure for2 hours, the above-identified compound (24.7 mg) was obtained as aslightly brownish amorphous product. Rf=0.25 (methanol/chloroform of1/10).

EXAMPLE 44(±)-N'-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide

A. Synthesis of(±)-N'-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 44)

In the same manner as in the case of Intermediate 43 in the step C ofExample 42, a solution of 486 mg of Intermediate 42, 290,4 mg ofIntermediate 17 and 1.44 ml of Hunig Base (supplied from the firmAldrich) in 1.3 ml of dimethylacetamide was agitated at 60° C. for 16hours. To the reaction mixture, ethyl acetate and water were added toeffect extraction and the aqueous phase was further extracted with ethylacetate three times. The united organic phase was dried and the solventwas distilled off under a reduced pressure. The resulting residue waspurified by a column chromatography(chloroform--methanol/chloroform=1/49), whereby 75.3 mg of theabove-identified compound were obtained. Rf=0.51 (methanol/chloroform of1/10).

B. Synthesis of(±)-N'-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]2-benzyloxyphenyl]-N,N-dimethylsulfamide

To a solution of 75.3 mg of Intermediate 44 in 3.3 ml of anhydroustetrahydrofuran, 43 μl of acetic acid and 667 μl of 1 M solution oftetrabutyl ammonium fluoride in tetrahydrofuran were added and themixture was agitated at room temperature for 1 hour. The reactionmixture was diluted with ethyl acetate and was washed with saturatedaqueous sodium bicarbonate solution and then with saturated aqueoussodium chloride solution, followed by drying over anhydrous sodiumsulfate, whereupon the solvent was distilled off under a reducedpressure. The resulting residue was triturated with ethanol, whereuponthe above-identified compound (47.1 mg) was obtained as a white powderyproduct. Rf=0.25 (methanol/chloroform of 1/10).

EXAMPLE 45(±)-N'-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

The compound of Example 44 was dissolved in 4.8 ml of methanol andthereto were added 0.78 ml of 0.1 N hydrogen chloride/ethanol and 25 mgof 10% palladium/carbon black and the mixture was agitated under 1 atmhydrogen gas for 2.2 hours. The catalyst was filtered and washed withhot methanol, whereupon the solvent was distilled off under a reducedpressure. The residue was triturated with diethyl ether and wascollected by filtration. By drying at 50° C. under a reduced pressurefor 2 hours, the above-identified compound (40.6 mg) was obtained as aslightly brownish powdery product. Rf=0.05 (methanol/chloroform of1/10).

EXAMPLE 46(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-nitrophenyl)]ethanolhydrochloride

To a mixed solution of 678.6 mg of HBr addition salt of Intermediate 2and 371 μl of triethylamine in 45 ml of anhydrous acetonitrile and 4.5ml of anhydrous dimethylformamide, a solution of 539 mg of2-bromo-1-(3-nitrophenyl)ethanone [prepared by the method reported by A.A. Larsen et al in J. Med. Chem., 9, 88-97 (1966)] in 20 ml of anhydrousacetonitrile were added under argon atmosphere at 0° C. and the mixturewas agitated for 1 hour. This mixture was warmed to the room temperature(ca. 22° C.) and agitation was continued for further 2 hours. To thismixture, a solution of 434 mg of sodium borohydride in 20 ml of absoluteethanol was added at room temperature. After agitation for 1 hour, thereaction was terminated with 1.0 N hydrochloric acid (pH 4), whereupon1.1 ml of ethanolamine were added thereto. After agitation for 10minutes, the mixture was diluted with ethyl acetate and the organiclayer was washed thrice with saturated aqueous sodium chloride solutionand dried, whereupon the solvent was distilled off under a reducedpressure to obtain 0.93 g of crude product. By recrystallization fromethyl acetate/ethanol, unreacted starting amine compound was removed andthe filtrate was concentrated, whereupon the resulting residue waspurified by a PTLC (development with methanol/chloroform of 1/10),whereby 77.4 mg of free amine compound were obtained. Rf=0.32(methanol/chloroform of 1/10).

By adding thereto 0.1 N hydrogen chloride/ethanol (1.1 equivalentamount), it was converted into hydrochloride salt (the above-identifiedcompound), followed by evaporating off of the solvent under a reducedpressure. Diethyl ether was added to the resulting residue and thedeposited precipitate was subjected to recrystallization from ethanol,followed by drying at 50° C. under a reduced pressure, whereby theabove-identified compound was obtained as a powdery product.

EXAMPLE 47(±)2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-aminophenyl)]ethanolhydrochloride

To a solution of 43.9 mg of the compound of Example 46 in 2 ml ofmethanol, 38.3 mg of iron powder and 90 μl of concentrated hydrochloricacid were added and the mixture was agitated at room temperature for 4hours. The reaction mixture was diluted with water and the pH thereofwas adjusted with 5 N NaOH at 10, whereupon extraction with ethylacetate was carried out. After drying the organic layer, the solvent wasdistilled off under a reduced pressure, whereby 50 mg of a crude productwere obtained. This was purified by a PTLC (development withmethanol/ethyl acetate of 1/4), whereby 16 mg of free amine compoundwere obtained. Rf=0.30 (methanol/ethyl acetate of 1/4).

This was converted into hydrochloride salt (the above-identifiedcompound) by adding 0.1 N hydrogen chloride/ethanol (1.1 equivalentamount) and the solvent was distilled off under a reduced pressure. Tothe resulting residue, diethyl ether was added and the depositedprecipitate was recrystallized from ethanol, followed by drying at 50°C. under a reduced pressure, whereupon the above-identified compound wasobtained as a powdery product.

EXAMPLE 48(±)-N'-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]-N,N-dimethylsulfamidehydrochloride

The reaction and the after-treatments were followed as in Example 46except that 710 mg of2-brom-1-[3-[(dimethylsulfamoyl)amino]phenyl]ethanone [prepared by themethod reported by A. A. Larsen et al in J. Med. Chem., 9, 88-97 (1966)]were employed and the resulting residue was purified by a PTLC(development with methanol/ethyl acetate of 1/4), whereby 112.2 mg offree amine compound were obtained. Rf=0.52 (methanol/ethyl acetate of1/3).

This was converted into hydrochloride salt (the above-identifiedcompound) by adding 0.1 N hydrogen chloride/ethanol (1.1 equivalentamount) and the solvent was distilled off under a reduced pressure. Tothe resulting residue, diethyl ether was added and the depositedprecipitate was recrystallized from ethanol, followed by drying at 50°C. under a reduced pressure, whereupon the above-identified compound(93.2 mg) was obtained as a powdery product.

EXAMPLE 49(±)-N-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamidehydrochloride

According to the procedures described in Example 1, 500 mg ofIntermediate 17 and 1.06 g of Intermediate 3 (70% purity) were subjectedto coupling reaction and the resulting product was then subjected toreduction using 359 mg of sodium borohydride, whereupon the reactionmixture was purified by a silicagel column chromatography(methanol/chloroform of 1/9), to obtain 245 mg of free amine product ofthe above-identified compound. Rf=0.24 (methanol/chloroform of 1/10). Apart (97 mg) of it was converted into hydrochloride salt (100 mg) with0.1 N hydrogen chloride/ethanol.

EXAMPLE 50(±)-N-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

According to the procedures described in Example 2, the compound ofExample 49 (100 mg) was dissolved in 10.5 ml of methanol and subjectedto a hydrogenolysis using 49.5 mg of 10% palladium/carbon black. Thecatalyst was filtered on celite at room temperature and washed with hotmethanol. After the filtrate and the washed liquor were broughttogether, the solvent was distilled off under a reduced pressure,whereby above-identified compound (77.5 mg) was obtained. Rf=0.03(methanol/chloroform of 1/10).

EXAMPLE 51(±)-N-[5-[2-[2-(9H-7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamidehydrochloride

72.1 mg of the free amine compound of Example 49 were dissolved in 10 mlof 10% solution of hydrogen chloride/methanol and was agitated at roomtemperature for 41 hours. The deposited precipitate was filtered off andwashed with diethyl ether, followed by drying (40 minutes) under areduced pressure at 50° C. to obtain the above-identified compound (49mg). Rf 0.27 (methanol/chloroform of 1/10).

EXAMPLE 52(±)-N-[5-[2-[2-(9H-7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

According to the procedures described in Example 2, the compound ofExample 51 (49 mg) was dissolved in 5.4 ml of methanol and subjected toa hydrogenolysis using 10% Pd-C (25.9 mg). The catalyst was filtered oncelite at room temperature and washed with hot methanol. After thefiltrate and the washed liquor were brought together, the solvent wasdistilled off under a reduced pressure, whereby the above-identifiedcompound (43.1 mg) was obtained. Rf=0.22 (methanol/ethyl acetate of1/3).

EXAMPLE 53(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-2-propanesulfonamidehydrochloride

A. Synthesis of2-bromo-1-[4-benzyloxy-3-[(isopropylsulfonyl)amino]phenyl]ethanone(Intermediate 45)

The above-identified Intermediate was produced (2.03 g, ca. 70% purity)in two process steps from 1-(3-amino-4-benzyloxyphenyl)ethanone (2 g) inthe same manner as in the case of Intermediate 3 (though, brominationwas performed according to the method described in the step A of Example29) except that isopropylsulfonyl chloride was employed instead ofmethanesulfonyl chloride. Rf=0.19 (chloroform).

B. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-2-propanesulfonamidehydrochloride

According to the procedures described in Example 1, 1.43 g ofIntermediate 45 (70% purity) and 686 mg of Intermediate 2 were subjectedto coupling reaction and, subsequently to reduction using 650 mg ofsodium borohydride, whereupon the reaction mixture was purified by asilica gel chromatography (methanol/chloroform of 11/89), to obtain 369mg of free amine product of the above-identified compound. Rf=0.49(methanol/chloroform of 1/5). This was converted into hydrochloride saltwith 0.1 N hydrogen chloride/ethanol.

EXAMPLE 54(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-2-propanesulfonamidehydrochloride

According to the procedures described in Example 2, the compound ofExample 53 (369 mg) was dissolved in 39.9 ml of methanol and subjectedto a hydrogenolysis using 10% Pd-C (190 mg). The catalyst was filteredon celite at room temperature and washed with hot methanol. After thefiltrate and the washed liquor were brought together, the solvent wasdistilled off under a reduced pressure, whereby the above-identifiedcompound (267 mg) was obtained. Rf=0.27(methanol/ethyl acetate of 1/3).

EXAMPLE 55(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

A. Synthesis of(±)-N-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-fluorophenyl]methanesufonamide(Intermediate 46)

The reaction and after-treatment were performed in accordance with theprocedures described in the steps A and B of Example 42, whereby theabove-identified compound (10.22 g) was obtained from Intermediate 9(7.48 g). Rf=0.36 (ethyl acetate/n-hexane of 1/3).

B. Synthesis of(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 47)

The reaction and after-treatment were performed in accordance with theprocedures described in the step C of Example 42, whereby theabove-identified compound (648 mg) was obtained from Intermediate 46(819 mg) and Intermediate 5 (500 mg). Rf=0.44 (methanol/chloroform of1/10).

C. Synthesis of(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

To a solution of 648 mg of Intermediate 47 in 30 ml of tetrahydrofuran,2.15 ml of 4 N solution of hydrogen chloride/dioxane were added and themixture was agitated at room temperature for 1 hour, whereupon 30 ml ofdiethyl ether were added thereto and the crystals were collected byfiltration and dried under a reduced pressure to obtain 408.8 mg of theabove-identified compound. Rf=0.61 (methanol/ethyl acetate of 1/3).

EXAMPLE 56(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide hydrochloride

A. Synthesis of(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 48)

The reaction and after-treatment were performed in accordance with theprocedures described in the step C of Example 42, whereby theabove-identified compound (581.8 mg) was obtained from Intermediate 46(811 mg) and Intermediate 39 (500 mg). Rf=0.52 (methanol/chloroform of1/10).

B. Synthesis of(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

To a solution of 581.8 mg of Intermediate 48 in 30 ml oftetrahydrofuran, 1.88 ml of 4 N solution of hydrogen chloride/dioxanewere added and the mixture was agitated at room temperature for 1 hour,whereupon 30 ml of diethyl ether were added thereto and the crystalswere collected by filtration and dried under a reduced pressure toobtain 412 mg of the above-identified compound. Rf=0.50 (methanol/ethylacetate of 1/3).

EXAMPLE 57(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

A. Synthesis of(±)-N-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 49)

The reaction and after-treatment were performed in accordance with theprocedures described in the steps A and B of Example 42,whereby theabove-identified compound (1.24 g) was obtained from Intermediate 13(1.72 g). Rf=0.65 (ethyl acetate/n-hexane of 1/2).

B. Synthesis of(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 50)

The reaction and after-treatment were performed in accordance with theprocedures described in the step C of Example 42, whereby theabove-identified compound (544 mg) was obtained from Intermediate 49(873 mg) and Intermediate 5 (500 mg). Rf=0.49 (methanol/ethyl acetate of1/10).

C. Synthesis of(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

To a solution of 544 mg of Intermediate 50 in 30 ml of tetrahydrofuran,1.75 ml of 4 N solution of hydrogen chloride/dioxane were added and themixture was agitated at room temperature for 1 hour, whereupon 30 ml ofdiethyl ether were added thereto and the crystals were collected byfiltration and dried under a reduced pressure to obtain 296.8 mg of theabove-identified compound. Rf=0.67 (methanol/ethyl acetate of 1/3).

EXAMPLE 58(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

A. Synthesis of(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl] -2-chlorophenyl]methanesulfonamide (Intermediate 51)

The reaction and after-treatment were performed in accordance with theprocedures described in the step C of Example 42, whereby theabove-identified compound (122 mg) was obtained from Intermediate 49(480 mg) and Intermediate 39 (249.8 mg). Rf=0.45 (ethyl acetate/hexaneof 2/1).

B. Synthesis of(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

To a solution of 122 mg of intermediate 51 in 6 ml of tetrahydrofuran,0.38 ml of 4 N solution of hydrogen chloride/dioxane was added and themixture was agitated at room temperature for 1 hour, whereupon diethylether was added thereto and the crystals were collected by filtrationand dried under a reduced pressure to obtain 86.7 mg of theabove-identified compound. Rf=0.76 (methanol/ethyl acetate of 1/3).

EXAMPLE 59(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]-N,N-dimethylsulfamidehydrochloride

A. Synthesis of 1-[4-fluoro-3-[(dimethylsulfamoyl)amino]phenyl]ethanone(Intermediate 52)

To a solution of 1 g of Intermediate 7 in 7.2 ml of pyridine, 708 g 1 ofdimethylaminosulfonyl chloride were added at room temperature. Afteragitation for 3 days, the mixture was poured into 50 ml of water andextraction with chloroform was carried out. The organic layer was washedwith saturated aqueous sodium chloride solution and dried, followed byevaporating under a reduced pressure to obtain a crude product. Then,the above reaction and after-treatment were carried out once more underthe same condition and the resulting crude product was purified by acolumn chromatography (2/1: n-hexane/ethyl acetate), whereby 1.1 g ofabove-identified compound were obtained. Rf=0.21 (ethyl acetate/n-hexaneof 1/2).

B. Synthesis of2-bromo-1-[4-fluoro-3-[(dimethylsulfamoyl)amino]phenyl]ethanone(Intermediate 53)

To a solution of 1.1 g of Intermediate 52 in 10 ml of 1,4-dioxane, 229μl of bromine were added under agitation. This mixture was warmed to 60°C. and was agitated for 2.5 hours. After cooling down to roomtemperature, water was added thereto and extraction with ethyl acetatewas carried out, whereupon the organic layer was washed saturatedaqueous sodium chloride solution and dried, followed by concentrationunder a reduced pressure to obtain the above-identified compound as acrude product (1.588 g). Rf=0.52 (ethyl acetate/n-hexane of 1/1).

C. Synthesis of(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]-N,N-dimethylsulfamidehydrochloride

A modification of the procedures described in the step D of Example 1was employed, in which a solution of 1.58 g of Intermediate 53 in 15 mlof anhydrous acetonitrile were added to a solution of 632 mg ofIntermediate 2 in a mixed solvent composed of 30 ml of anhydrousacetonitrile and 15 ml of anhydrous dimethylformamide under argonatmosphere at 0° C., whereupon 824 μl of triethylamine were addedthereto and the mixture was warmed to the room temperature (ca. 22° C.)and was agitated for 50 minutes.

To this mixture was then added a solution of 903 mg of sodium borohyridein 30 ml of absolute ethanol at room temperature. After agitation for 70minutes, the reaction was terminated using 1 N hydrochloric acid (pH 4)and thereto was added 1.35 ml of ethanolamine. After agitation for 10minutes, the mixture was diluted with 200 ml of ethyl acetate, organiclayer was rinsed with saturated aqueous sodium chloride solution threetimes and, then, dried, whereupon it was evaporated under a reducedpressure to obtain a crude product. This was purified by a columnchromatography (methanol/chloroform of 1/20), whereby 276 mg of freeamine product of the above-identified compound were obtained. Rf=0.66(10% conc. aq. ammonia-containing methanol/ethylacetate of 1/4).

To this, 1.l equivalent amount of 0.1 N hydrogen chloride/ethanol wereadded to convert it into hydrochloride salt (the above-identifiedcompound), from which the solvent was distilled off under a reducedpressure. To the resulting residue was added ethanol/ethyl acetate, thethereby deposited precipitate was isolated by filtration and was driedunder a reduced pressure at 50° C., whereby 188.2 mg of theabove-identified compound were obtained as a powdery product.

EXAMPLE 60(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]-N,N-dimethylsulfamidehydrochloride

A. Synthesis of 1-[4-chloro-3-[(dimethylsulfamoyl)amino]phenyl]ethanone(Intermediate 54)

To a solution of 1 g of Intermediate 11 in 6.5 ml of pyridine, 640 μl ofdimethylsulfamoyl chloride were added at room temperature and themixture was agitated for 28 hours. After heating the mixture at 40° C.for 65 hours, this was poured into water and extraction with chloroformwas carried out. The organic layer was washed with saturated aqueoussodium chloride solution and dried, followed by evaporating under areduced pressure to obtain a crude product. This was purified by acolumn chromatography (n-hexane/ethyl acetate of 4/1), whereby 865 mg ofthe above-identified compound were obtained. Rf=0.24 (ethylacetate/n-hexane of 1/2).

B. Synthesis of2-bromo-1-[4-chloro-3-[(dimethylsulfamoyl)amino]phenyl]ethanone(Intermediate 55)

To a solution of 860 mg of Intermediate 54 in 9 ml of 1,4-dioxane, 168μl of bromine were added under agitation. This mixture was warmed to 60°C. and was agitated for 1.5 hours. After cooling down to roomtemperature, water was added thereto and extraction with ethyl acetatewas carried out,whereupon the organic layer was washed saturated aqueoussodium chloride solution and dried, followed by evaporating under areduced pressure to obtain the above-identified compound as a crudeproduct (1.05 g). Rf=0.55(ethyl acetate/n-hexane of 1/1).

C. Synthesis of(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]-N,N-dimethylsulfamidehydrochloride

According to the procedures described in the step C of Example 59, theIntermediate 2 (447 mg) was reacted with the Intermediate 55 (1.05 g),followed by after-treatment and purification by a column chromatography(methanol/chloroform of 1/20) and further by a PTLC (10% conc. aq.ammonia-containing methanol/ethyl acetate of 1/4), whereby 251.1 mg offree amine product of the above-identified compound were obtained.Rf=0.67 (10% conc. aq. ammonia-containing methanol/ethyl acetate of1/4).

To this, 1.1 equivalent amount of 0.1 N hydrogen chloride/ethanol wereadded to convert it into hydrochloride salt (the above-identifiedcompound), from which the solvent was distilled off under a reducedpressure. To the resulting residue was added ethanol/ethyl acetate andthe thereby deposited precipitate was isolated by filtration and wasdried under a reduced pressure at 50° C., whereby 253.9 mg of theabove-identified compound were obtained as a powdery product.

EXAMPLE 61(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-3-benzyloxyphenyl]methanesulfonamide

A. Synthesis of 1-(3,5-dinitrophenyl)ethanone (Intermediate 56)

To a solution of 8 ml of dimethyl malonate in 70 ml of anhydroustetrahydrofuran, 78 ml of 0.92 M methyl magnesiumbromide/tetrahydrofuran (supplied from the firm Aldrich) were addeddropwise over a period of 30 minutes at a temperature of -10° C. orlower under argon atmosphere. Agitation was continued for further 15minutes and, then, a solution of 8.0 g of 3,5-dinitrobenzoyl chloride(supplied from Tokyo Chemical Industry Co.,Ltd.) in 35 ml of chloroformwas added dropwise thereto over a period of 15 minutes. The temperatureof the reaction mixture was permitted to elevate to room temperature andagitation was continued for further 59 hours. The solvent was evaporatedoff from the reaction mixture under a reduced pressure and the resultingamorphous yellow residue (36.72 g) was dissolved in a mixture of 42 mlof acetic acid/35 ml of water, whereto 5 ml of concentrated sulfuricacid were added and the mixture was agitated with heating under refluxfor 5 hours. This reaction mixture was poured into 300 ml of ice waterand the deposited precipitate was separated by filtration. This waswashed with water and dried (6.35 g) at room temperature under a reducedpressure and was recrystallized from ethanol (5 ml), whereby 2.1 g ofthe above-identified compound were obtained. Rf=0.79 (ethylacetate/n-hexane of 1/2).

B. Synthesis of 1-(3-amino-5-nitrophenyl)ethanone (Intermediate 57)

To a solution of 503 mg of Intermediate 56 in 10 ml of acetic acid, asolution of 1.43 g of stannous chloride (anhydrous) in 5 ml ofconcentrated hydrochloric acid were added dropwise over a period of 5minutes with agitation under cooling with salt/icecoolant. The mixturewas removed from the cooing bath and was agitated for three hours whilethe temperature was permitted to elevate gradually to room temperature.This reaction mixture was poured into 100 ml of saturated aqueous sodiumbicarbonate solution and the pH was adjusted at 8 by adding a furtheramount of saturated aqueous sodium bicarbonate solution, whereuponextraction with ethyl acetate (three times with each 50 ml) wasperformed. The organic layer was washed with saturated aqueous sodiumchloride solution and dried. followed by evaporating off of the solventunder a reduced pressure to obtain 160 mg of the above-identifiedcompound. Rf=0.51 (ethyl acetate/n-hexane of 1/2).

C. Synthesis of 1-(3-hydroxy-5-nitrophenyl)ethanone (Intermediate 58)

350 mg of Intermediate 57 were dissolved in 10 ml of sulfuric acidsolution (prepared by adding 5 ml of water to 5 ml of concentratedsulfuric acid) and the mixture was agitated under ice-cooling, whereto 5ml of an aqueous solution of sodium nitrite (140 mg) were added dropwiseover a period of 5 minutes. After agitation for further 25 minutes, 10ml of the above sulfuric acid were added thereto and the mixture wasagitated with heating at 120° C. under reflux for 30minutes. Aftercooling down to room temperature, extraction with ethyl acetate (twicewith each 40 ml) was performed. The organic layer was dried and thesolvent was distilled off under a reduced pressure, whereby 293 mg of acrude product were obtained. This was purified by a silica gelchromatography (elution with chloroform--methanol/chloroform of3/97-5/95), whereby 154 mg of the above-identified compound wereobtained. Rf=0.40 (methanol/chloroform of 1/9).

D. Synthesis of 1-(3-benzyloxy-5-nitrophenyl)ethanone (Intermediate 59)

154 mg of Intermediate 58 were dissolved in 5 ml of anhydrousdimethylformamide and thereto were added 360 mg of anhydrous potassiumcarbonate, 0.22 ml of benzyl bromide and 130 mg of sodium iodide,successively, and the mixture was agitated for 11.5 hours. Then, 10 mlof water were added to the reaction mixture to terminate the reactionand thereto were added further 50 ml of water, whereupon extraction withethyl acetate (twice with each 50 ml) was performed. Organic layer waswashed with 100 ml of water and with saturated aqueous sodium chloridesolution, successively, followed by drying and distilling off of thesolvent under a reduced pressure, whereby 277 mg of a crude product wereobtained. This was purified by a silica gel chromatography (elution withethyl acetate/n-hexane of 1/9), whereby 140 mg of the above-identifiedcompound were obtained. Rf=0.91 (methanol/chloroform of 1/9).

E. Synthesis of 1-(3-amino-5-benzyloxyphenyl)ethanone (Intermediate 60)

140 mg of Intermediate 59 were dissolved in 20 ml of methanol andthereto were added 5 mg of platinum oxide under argon atmosphere,whereupon the reaction system was replaced with hydrogen gas underice-cooling. The mixture was agitated for 11.5 hours under ice-cooling,whereupon the reaction system was replaced with argon and 20 ml ofchloroform were added thereto. After the catalyst has been removed byfiltration, the solvent was distilled off from the filtrate under areduced pressure, whereby 116 mg of the above-identified compound wereobtained. Rf=0.82 (methanol/chloroform of 1/9).

F. Synthesis of 1-[3-benzyloxy-5-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 61)

According to the method reported by A. A. Larsen in J. Med. Chem., 10,462-472 (1967), reaction and after-treatment were performed, whereby 142mg of the above-identified compound were obtained from 116 mg ofIntermediate 60 and 40 μl of methanesulfonyl chloride throughpurification by silica gel chromatography (elution withmethanol/chloroform of 5/95). Rf=0.47 (methanol/chloroform of 1/9).

G. Synthesis of2-bromo-1-[3-benzyloxy-5-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 62)

In the same manner as the procedures described in the step A of Example29, 172 mg of the above-identified compound were obtained from 140 mg ofIntermediate 61 and 223 mg of cupric bromide. Rf=0.78 (ethylacetate/n-hexane of 1/1).

H. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-3-benzyloxyphenyl]methanesulfonamide

In accordance with the procedures described in the step D of Example 1,55 mg of the above-identified compound were obtained from

170 mg of Intermediate 62 and 95 mg of Intermediate 2. Rf=0.28(methanol/chloroform of 1/9).

EXAMPLE 62(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-3-hydroxyphenyl]methanesulfonamidehydrochloride

In accordance with the procedure described in Example 2, 55 mg of thecompound of Example 61 were subjected to a hydrogenolysis using 10%palladium/carbon black (27.5 mg), whereby 30.6 mg of theabove-identified compound were obtained. Here, however, the crudeproduct was purified in a usual manner by converting it intohydrochloride salt which was recrystallized from methanol/ethyl acetate.Rf=0.05(methanol/chloroform of 1/9).

EXAMPLE 63(±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

A. Synthesis of 1-(2-hydroxy-3-nitrophenyl)ethanone (Intermediate 63)and 1-(2-hydroxy-5-nitrophenyl)ethanone (Intermediate 64)

13.2 g of 2-hydroxyacetophenone (supplied from the firm Aldrich) weredissolved in 140 ml of concentrated sulfuric acid under ice-cooling,whereto 9.66 g of potassium nitrate were added. The mixture was agitatedat 10-15° C. for 105 minutes, whereto a total of 2.8 g of potassiumnitrate were further added in three portions over a period of 8 hoursuntil the starting material has been consumed. Then the mixture wasagitated for 14 hours under ice-cooling and the resulting reactionmixture was poured into two liters of ice-water mixture, followed byextraction with ethyl acetate (twice with each 500 ml), whereupon theorganic layer was washed with saturated aqueous sodium chloride solutionand dried, before the solvent was distilled off under a reduced pressureto obtain 19.23 g of a crude product. This was purified by a silica gelchromatography, whereby 6.0 g of Intermediate 64 were obtained fromelution fractions with ethyl acetate/n-hexane of 1/9 and 9.5 g ofIntermediate 63 were obtained from elution fractions with ethylacetate/n-hexane of 1/4.

Intermediate 63: Rf=0.19 (ethyl acetate/n-hexane of 1/4)

Intermediate 64: Rf=0.49 (ethyl acetate/n-hexane of 1/4)

B. Synthesis of 1-(2-methoxy-3-nitrophenyl)ethanone (Intermediate 65)

2.29 g of Intermediate 63 were dissolved in 20 ml of anhydrousdimethylformamide and thereto were added 5.2 g of anhydrous potassiumcarbonate, and 1.56 ml of methyl iodide, successively, whereupon themixture was agitated for 18 hours. Then, 50 ml of water were added tothe reaction mixture to terminate the reaction, whereupon extractionwith ethyl acetate (6 times with each 50 ml) was performed. The organiclayer was washed with saturated aqueous sodium chloride solution,followed by drying and distilling off of the solvent under a reducedpressure, whereby 2.29 g of a crude product were obtained. This wasfurther dried under a reduced pressure with vacuum pump, whereby 1.87 gof the above-identified compound were obtained. Rf=0.58 (ethylacetate/n-hexane of 1/2).

C. Synthesis of 1-(3-amino-2-methoxyphenyl)ethanone (Intermediate 66)

1.87 g of Intermediate 65 were dissolved in 150 ml of methanol andthereto were added 90 mg of platinum oxide under argon atmosphere,whereupon the reaction system was replaced with hydrogen gas underice-cooling. The mixture was agitated at room temperature for 5 hoursand the reaction system was replaced with argon gas, followed byaddition of 50 ml of chloroform. The catalyst was filtered off and thesolvent was distilled off from the filtrate under a reduced pressure,whereby 1.59 g of the above-identified compound were obtained. Rf=0.74(methanol/chloroform of 1/9).

D. Synthesis of 1-[2-methoxy-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 67)

According to the method reported by A. A. Larsen in J. Med. Chem., 10,462-472 (1967), the above compound was produced from Intermediate 66(1.59 g) and methanesulfonyl chloride (750 μl). Here, however, thefollowing alteration was incorporated in the purification step from thereaction mixture. Thus, the reaction was terminated with water (50 ml)and the mixture was agitated for 12 hours before extraction with ethylacetate (once with 50 ml and twice with each 30 ml) with subsequentwashing with 1 N hydrochloric acid (twice with each 25 ml) and withsaturated aqueous sodium chloride solution, successively, followed bydistilling off of the solvent under a reduced pressure, whereby theabove-identified compound was obtained (1.93 g). Rf=0.55(methanol/chloroform of 1/19).

E. Synthesis of1-[2-methoxy-3-[N-benzyl-N-(methylsulfonyl)amino]phenyl]ethanone(Intermediate 68)

1.93 g of Intermediate 67 were dissolved in 15 ml of anhydrousdimethylformamide and thereto were added at room temperature 3.32 g ofanhydrous potassium carbonate, 1.9 ml of benzyl bromide and 1.2 g ofsodium iodide, successively, and the mixture was agitated for 14 hours.Then, 50 ml of water were added to the reaction mixture to terminate thereaction, whereupon extraction with ethyl acetate (thrice with each 40ml) was performed. Organic layer was washed with water (twice with each50 ml) and with saturated aqueous sodium chloride solution,successively, followed by drying and distilling off of the solvent undera reduced pressure, whereby 3.04 g of a crude product were obtained.This was purified by a silica gel chromatography (elution with ethylacetate/n-hexane of 1/4-1/2), whereupon fractions containing the targetcompound were processed by evaporating and recrystallization from ethylacetate/n-hexane to obtain the above-identified compound (2.00 g).Rf=0.75 (methanol/chloroform of 1/19).

F. Synthesis of2-bromo-1-[2-methoxy-3-[N-benzyl-N-(methylsulfonyl)amino]phenyl]ethanone(Intermediate 69)

In the same manner as the procedures described in the step A of Example29, 438 mg of the above-identified compound were obtained from 333 mg ofIntermediate 68 and 491 mg of cupric bromide. Rf=0.36 (ethylacetate/n-hexane of 1/2).

G. Synthesis of(±)-N-benzyl-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-methoxyphenyl]methanesulfonamide(Intermediate 70)

According to the procedures described in the step D of Example 1, theabove-identified compound (150 mg) was obtained from Intermediate 69(438 mg) and Intermediate 2 (215 mg). Rf=0.74 (methanol/chloroform of1/9).

H. Synthesis of(±)-N-benzyl-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride (Intermediate 71)

To a solution of 100 mg of Intermediate 70 in 10 ml of anhydrousdichloromethane, 0.60 ml of 1 M solution of boron tribromide indichloromethane (supplied from the firm Aldrich) was added dropwiseunder cooling with dry ice/acetone coolant. The mixture was agitated assuch for 30 minutes and, then, agitation was continued for further 30minutes under ice-cooling. The reaction was terminated by addingsaturated aqueous sodium bicarbonate solution to the reaction mixtureand extraction with ethyl acetate was carried out (four times with each30 ml). The organic layer was washed with saturated aqueous sodiumchloride solution with subsequent drying, whereupon the solvent wasdistilled off under a reduced pressure. The resulting residue waspurified by a silica gel chromatography (elution with chloroform/ethylacetate/10% of conc. aq. ammonia-containing methanol of 16/3/1-6/3/1),whereby 69 mg of free amine product of the above-identified compoundwere obtained, Rf=0.47 (methanol/chloroform of 1/9).

This was converted into hydrochloride salt using 0.1 N HCl/ethanol,whereby 28 mg of the above-identified compound were obtained byrecrystallization from methanol/ethyl acetate. Here, 38 mg of theabove-identified compound were recovered also from the filtrate.

I. Synthesis of(±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

According to the procedures described in Example 2, the above-identifiedcompound (17.3 mg) was obtained from Intermediate 71 and the recoveredproduct from the filtration (total sum of 55 mg) by subjecting them to ahydrogenolysis using 10% palladium/carbon black (55 mg) for 13 hourswith subsequent recrystallization of the resulting crude product (25 mg)from methanol/ethyl acetate. Rf=0.41 (methanol/chloroform of 1/9).

EXAMPLE 64(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamidehydrochloride

A. Synthesis of 1-(2-methoxy-5-nitrophenyl)ethanone (Intermediate 72)

The above-identified compound (2.50 g) was obtained by processingIntermediate 64 (2.36 g) resulting from the step A of Example 63 throughreaction and after-treatment in accordance with the procedures of thestep B of Example 63. Rf=0.37(ethyl acetate/n-hexane of 1/2).

B. Synthesis of 1-(5-amino-2-methoxyphenyl)ethanone (Intermediate 73)

The above-identified compound (2.13 g) was obtained by processingIntermediate 72 (2.50 g) through reaction and after-treatment inaccordance with the procedures of the step C of Example 63. Rf=0.38(methanol/chloroform of 1/19).

C. Synthesis of 1-[2-methoxy-5-[(methylsulfonylamino]phenyl]ethanone(Intermediate 74)

The above-identified compound (2.656 g) was obtained by processingIntermediate 73 (2.13 g) through reaction and after-treatment inaccordance with the procedures of the step D of Example 63. Rf=0.35(methanol/chloroform of 1/19).

D. Synthesis of1-[2-methoxy-5-[N-benzyl-N-(methylsulfonyl)amino]phenyl]ethanone(Intermediate 75)

A crude product (4.29 g) was obtained by processing Intermediate 74(2.65 g) through reaction and after-treatment in accordance with theprocedures of the step E of Example 63. By purifying this crude productby a silica gel column chromatography (elution with ethylacetate/n-hexane of 1/4-1/2-2/3) and processing the fractions containingthe target compound by evaporating and recrystallization from ethylacetate/n-hexane, the above-identified compound (2.553 g) was obtained.Rf=0.68 (methanol/chloroform of 1/19).

E. Synthesis of2-bromo-1-[2-methoxy-5-[N-benzyl-N-(methylsulfonyl)amino]phenyl]ethanone(Intermediate 76)

In the same manner as the procedures described in the step A of Example29, the above-identified compound (436 mg) was obtained fromIntermediate 75 (333 mg) and cupric bromide (491 mg). Rf=0.28 (ethylacetate/n-hexane of 1/2).

F. Synthesis of(±)-N-benzyl-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-methoxyphenyl]methanesulfonamide(Intermediate 77)

In accordance with the procedures described in the step D of Example 1,the above-identified compound (70 mg) was obtained from Intermediate 76(436 mg) and Intermediate 2 (215 mg). Rf=0.52 (methanol/chloroform of1/9).

G. Synthesis of(±)-N-benzyl-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamidehydrochloride (Intermediate 78)

The free base product (39 mg) was obtained by processing Intermediate 77(70 mg) through reaction and after-treatment in accordance with theprocedures of the step H of Example 63 and purification by a silicagelchromatography (elution with chloroform/ethyl acetate/10% of conc. aq.ammonia-containing methanol of 16/3/1-6/3/1). Rf=0.50(methanol/chloroform of 1/9). By converting this product intohydrochloride salt using 0.1 N hydrogen chloride/ethanol with subsequentrecrystallization from methanol/ethyl acetate, the above-identifiedcompound (17 mg) was obtained.

H. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamidehydrochloride

According to the procedures described in Example 2, Intermediate 78 andthe recovered product from the filtration (total sum of 30 mg) weretreated by subjecting them to a hydrogenolysis for 13 hours using 10%palladium/carbon black (30 mg) with subsequent trituration of theresulting crude product from methanol/ethyl acetate, whereby theabove-identified compound (9 mg) was obtained. Rf=0.34(methanol/chloroform of 1/9).

EXAMPLE 65(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamidehydrochloride

A. Synthesis of N-methyl-(2-benzyloxy-4-acetylbenzene) sulfonamide(Intermediate 80)

2.41 g of 1-(3-amino-4-benzyloxyphenyl)ethanone[prepared by the methodreported by A. A. Larsen et al in J. Med. Chem., 10, 462-472 (1967)]were dissolved in 5 ml of acetic acid and thereto were added 5 ml ofconcentrated hydrochloric acid. To this mixture, 7 ml of an aqueoussolution of sodium nitrite (1.0 g) were added over a period of 50minutes at -10° C. with agitation. Agitation was continued further for28 minutes under ice-cooling and thereto were added a solution of 3.5 mlof thionyl chloride in 6.5 ml of acetic acid and 3 ml of an aqueoussolution of cupric chloride dihydrate (720 mg), successively, whereuponthe mixture was agitated for 6 hours, while the temperature was allowedto return to room temperature. The deposited precipitate was separatedby filteration and was dissolved in chloroform, followed by waterwashing and drying with subsequent evaporating up to a volume of 50 mlunder a reduced pressure, whereby a solution of2-benzyloxy-5-acetylbenzenesulfonylchloride (Intermediate 79) inchloroform was prepared.

Thereto was added 1.0 ml of 40% aqueous solution of methylamine and themixture was agitated at room temperature for 16.5 hours. To thisreaction mixture, 50 ml of water were added and the organic layer wasseparated. The aqueous layer was extracted once with chloroform (50 ml)and the extract was brought together with the above organic layer andwas rinsed with saturated aqueous sodium chloride solution, followed bydrying, whereupon the solvent was distilled off under a reducedpressure. Resulting residue was purified by a silica gelchromatography(chloroform--methanol/chloroform of 1/19), whereby 200 mgof the above-identified compound were obtained. Rf=0.05 (chloroform).

B. Synthesis ofN-methyl-[2-benzyloxy-4-(2-bromoacetyl)benzenesulfonamide (Intermediate81)

In the same manner as the procedures described in the step A of Example29, the above-identified compound (248 mg) was obtained fromIntermediate 80 (200 mg) and cupric bromide (310 mg). Rf=0.83 (ethylacetate/n-hexane of 1/1).

C. Synthesis of(±)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamide

In the same manner as in the procedures described in the step D ofExample 1 except that a silicagel chromatography (methanol/ethyl acetateof 1/19-1/9) was employed for the purification of the crude product, theabove-identified compound (118 mg) was obtained from Intermediate 81(248 mg) and Intermediate 2 (136 mg). Rf=0.55 (methanol/chloroform of1/9).

EXAMPLE 66(±)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

In accordance with the procedure described in Example 2, the compound ofExample 65 (110 mg) were subjected to a hydrogenolysis using 10%palladium/carbon black (55 mg) for 1 hour, whereby the above-identifiedcompound (39 mg) was obtained. Rf=0.05 (methanol/chloroform of 1/9).

EXAMPLE 67(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanolhydrochloride

A. Synthesis of 2-benzyloxy-5-acetylbenzoic acid methyl ester(Intermediate 82)

1.94 g of 5-acetylsalicylic acid methyl ester (supplied from the firmAVOCADO) were dissolved in 15 ml of anhydrous dimethylformamide andthereto were added 4.2 g of anhydrous potassium carbonate, 2.5 ml ofbenzyl bromide and 3.3 g of sodium iodide, successively, whereupon themixture was agitated for 60 hours. The reaction was terminated by adding15 ml of water to the reaction mixture and the mixture was agitated withice-cooling. The deposited precipitate was separated by filtration,washed with water and dried under a reduced pressure at 50° C. (2.83 g).This was recrystallized from toluene/n-hexane and 2.54 g of theabove-identified compound were obtained. Rf=0.32 (ethyl acetate/n-hexaneof 1/2).

B. Synthesis of 2-benzyloxy-5-(2-bromoacetyl)benzoic acid methyl ester(Intermediate 83)

In the same manner as the procedures described in the step A of Example29, the above-identified compound (566 mg) was obtained fromIntermediate 82(1.42 g) and cupric bromide (151 mg). Rf=0.71(methanol/chloroform of 1/19).

C. Synthesis of(±)-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzoicacid methyl ester (Intermediate 84)

According to the procedures described in the step D of Example 1, theabove-identified compound (80 mg) was obtained from Intermediate 2 (154mg), triethylamine (150 μl), Intermediate 83 (191 mg) and sodiumborohydride (151 mg). Rf=0.24 (methanol/chloroform of 1/9).

D. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[4-benzyloxy-3-(hydroxymethyl)phenyl]ethanol(Intermediate 85)

To a suspension of 2 mg of lithium aluminum hydride in 5 ml of anhydroustetrahydrofuran, a solution of 34 mg of Intermediate 84 in 5 ml ofanhydrous tetrahydrfuran was added. After agitation for 30 minutes,reaction was terminated by adding 1 ml of ethyl acetate and 1 ml of 1 NHCl and the aqueous layer was adjusted at pH 10, whereupon extractionwith ethyl acetate(twice with each 20 ml) was performed. The organiclayer was dried and the solvent was distilled off under a reducedpressure, whereupon the resulting residue (28 mg) was purified by asilica gel chromatography (methanol/chloroform of 1/9-1/7) to obtain 24mg of the above-identified compound. Rf=0.05 (methanol/chloroform of1/9).

E. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanolhydrochloride

In accordance with the procedure described in Example 2, Intermediate 85(24 mg) was added to methanol (5 ml) and was subjected to ahydrogenolysis using 10% palladium/carbon black (12 mg) for 2.5 hours,whereby the above-identified compound (8.9 mg) was obtained. Rf=0.21(methanol/chloroform of 1/7).

EXAMPLE 68(±)-N-[3-[2-[2-(9H-6-(acetylamino)carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

A. Synthesis of(±)-N-[3-(2-bromo-1-hydroxyethyl)phenyl]methanesulfonamide (Intermediate86)

The above-identified compound (50.76 g) was obtained by processingIntermediate 14 (45 g) through reaction and after-treatment inaccordance with the procedures of synthesis of Intermediate 41. Rf=0.27(methanol/chloroform of 1/10).

B. Synthesis of(±)-N-[3-[2-iodo-1-(triethylsilyloxy)ethyl]phenyl]methanesulfonamide(Intermediate 87)

According to the method for synthesizing Intermediate 42, Intermediate86 (50.1 g) was dissolved in dried acetone (944 ml) and thereto wasadded sodium iodide (257.57 g) and the mixture was agitated with heatingunder reflux for 2.5 hours. Then, the mixture was cooled down to roomtemperature and was filtered, whereupon the filtrate was evaporated todryness under a reduced pressure. The resulting residue was subjected toextraction with 720 ml of dichloromethane and 720 ml of water, followedby washing of the organic layer with 23.5% (w/w) of aqueous sodiumhydrogen sulfite solution (twice), with water and with saturated aqueoussodium chloride solution, successively, and drying, whereupon thesolvent was distilled off under a reduced pressure. The residue wasfurther dried under a reduced pressure using a vacuum pump, whereby51.61 g of a viscous fluid product was obtained. This was dissolved in351 ml of anhydrous dimethylformamide at room temperature, whereto 28.3g of imidazole and 1.61 g of 4-dimethylaminopyridine and the resultingmixture was agitated for 15 minutes. Thereto were added 27.04 ml ofchlorotrimethylsilane all at once and the mixture was agitated at roomtemperature for 40 minutes. The resulting mixture was then diluted with840 ml of ethyl acetate and 336 ml of n-heptane and was then washed withwater (420 ml), with 2% aqueous solution of copper sulfate (twice witheach 420 ml), with water (420 ml) and finally with saturated aqueoussodium chloride solution (420 ml), successively, and dried, whereuponthe solvent was distilled off under a reduced pressure to obtain 68.25 gof the above-identified compound. Rf=0.48 (methanol/chloroform of 1/10).

C. Synthesis of 4-acetylaminocyclohexanone (Intermediate 88)

To a suspension of 20.85 g of trans-4-acetamidecyclohexanol in 21.6 mlof water under ice-cooling, Jone's Reagent prepared from 9.28 g ofcromium trioxide, 8.1 ml of concentrated sulfuric acid and 33.4 ml ofwater was added over a period of 8 minutes under ice-cooling. Theresulting mixture was agitated for further 5 hours under ice-cooling,whereupon it was stored in a refrigerator for 2 days. This was subjectedto extraction with chloroform (10 times with each 70 ml), followed bywashing with saturated aqueous sodium bicarbonate solution and drying,whereupon the solvent was distilled off under a reduced pressure. Theresulting residue was further dried at room temperature under a reducedpressure, whereby 8.45 g of the above-identified compound were obtained.Rf=0.40(methanol/chloroform of 1/10).

D. Synthesis of (±)-3-acetylamino-7-methoxy-1,2,3,4-tetrahydrocarbazole(Intermediate 89)

9.77 g of 3-methoxyphenylhydrazine hydrochloride (supplied from the firmACROS) and 8.58 g of Intermediate 88 were dissolved in 83 ml of ethanol,whereto 35 ml of 4 N hydrogen chloride/1,4-dioxane (supplied from thefirm Aldrich) were added and the mixture was heated under reflux for 3hours. The resulting mixture was cooled down to room temperature andprecipitate was filtered off and the solvent in the filtrate wasdistilled off under a reduced pressure. To the resulting residue,ethanol/n-heptane was added and the resulting mixture was evaporated todryness, whereupon the residue was dissolved in a small amount ofethanol, whereto water was added and the deposited precipitate wastriturated and isolated by filtration, followed by water washing anddrying at 42° C. under a reduced pressure. This was then treated bytrituration with small amount of ethanol, crystallization from ethylacetate (200 ml). filtration of crystals, washing with ethyl acetate anddrying under a reduced pressure at room temperature to obtain 5.188 g ofthe above-identified compound as primary crystals. Rf=0.45(methanol/chloroform of 1/10).

E. Synthesis of 9H-6-acetylamino-2-methoxycarbazole (Intermediate 90)

5.188 g of Intermediate 89 and 9.459 g of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (97%) were heated under refluxin benzene for 7.5 hours under argon atmosphere. The reaction mixturewas filtered with heating and the filtered cake was washed with hotbenzene. The filtrate and the washed liquor were brought together, fromwhich the solvent was distilled off under a reduced pressure. To theresulting residue, ethanol was added and the deposited product wasisolated by filtration, whereby 269 mg of the above-identified compound(primary crystals) were obtained. Rf=0.39 (methanol/chloroform of 1/10).

F. Synthesis of 9H-6-acetylamino-2-hydroxycarbazole (Intermediate 91)

269 mg of Intermediate 90 were added at 180° C. to pyridinehydrochloride (prepared by heating 5 ml of pyridine and 5 ml ofconcentrated hydrochloric acid at 180° C. for 1.5 hours to dehydrate)and the mixture was agitated with heating under reflux for 4 hours. Theresulting mixture was poured into 100 ml of ice and was then subjectedto extraction with ethyl acetate. The aqueous layer was adjusted at pH 7and was treated by a further extraction with ethyl acetate. Both organiclayers were brought together and are washed with saturated aqueoussodium chloride solution, followed by drying, whereupon the solvent wasdistilled off under a reduced pressure. The resulting residue (182.1 mg)was dissolve in pyridine (5 ml), whereto 1 ml of acetic anhydride wasadded and the mixture was agitated at room temperature for 12 hours. Theresulting mixture was diluted with 50 ml of water and was then subjectedto extraction with ethyl acetate, followed by washing with water andthen with saturated aqueous sodium chloride solution with subsequentdrying, whereupon the solvent was distilled off under a reducedpressure. The resulting residue was dissolved in 4 ml of methanol (MS3Agrade), whereto 1 ml of water and 0.5 ml of 5 N aqueous sodium hydroxidesolution were added and the mixture was agitated at room temperature for45 minutes. Then, the mixture was diluted with 40 ml of water andadjusted at pH 3 with 1N hydrochloric acid, whereupon extraction withethyl acetate was effected three times for this mixture. The resultingorganic layers were washed with saturated aqueous sodium chloridesolution with subsequent drying, followed by distilling off of thesolvent under a reduced pressure, whereby 163.8 mg of theabove-identified compound were obtained. Rf=0.10(methanol/chloroform of1/10).

G. Synthesis of9H-6-acetylamino-2-(2-benzyloxycarbonylaminoethoxy)carbazole(Intermediate 92)

According to the procedures described in the step B of Example 1, 520 mgof Intermediate 0 were added to a solution of 161 mg of Intermediate 91and 470 mg of potassium carbonate in dimethylformamide (1.7 ml) and themixture was agitated at room temperature for 11.5 hours with furtheragitation at 50° C. for 8 hours. Thereto were added ethyl acetate andwater, followed by extraction with ethyl acetate twice and washing withwater and with saturated aqueous sodium chloride solution, successively,drying and distilling off of the solvent under a reduced pressure,whereupon the resulting residue was purified by a column chromatography(methanol/chloroform of 3/100-6/100), whereby 105.8 mg of theabove-identified compound were obtained. Rf=0.37 (methanol/chloroform of1/10).

H. Synthesis of 2-(9H-6-acetylaminocarbazol-2-yloxy)ethylamine(Intermediate 93)

To 105,8 mg of Intermediate 92, 2.1 ml of 30% solution of hydrogenbromide in acetic acid were added and the mixture was agitated at roomtemperature for 1.5 hours. Thereto were added 50 ml of diethyl ether andthe deposited precipitate was isolated by filtration. This was dissolvedin water and the pH was adjusted at 10 with aqueous NaOH and wassubjected to extraction with ethyl acetate. After drying the organiclayer, the solvent thereof was distilled off under a reduced pressure,whereby 80.1 mg of the above-identified compound were obtained. Rf=0.05(methanol/chloroform of 1/5).

I. Synthesis of(±)-N-[3-[2-[2-[9H-6-(acetylamino)carbazol-2-yloxy]ethyamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

117.5 mg of Intermediate 87 and 80, 1 mg of Intermediate 93 weredissolved in 0.5 ml of anhydrous dimethylacetamide and thereto wereadded 493 μl of Hunig Base, whereupon the mixture was agitated at 60° C.for 27 hours under argon atmosphere. Then, the mixture was cooled downto room temperature and was diluted with ethyl acetate, followed bywashing water (twice) and then with saturated aqueous sodium chloridesolution and drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue was dissolved in ethyl acetateand the insoluble matter was filtered off, whereupon the filtrate wasevaporated under a reduced pressure. The resulting residue was subjectedto a primary purification by a silica gel chromatography(methanol/chlorofrom of 5/100-1/10).

Fractions containing a product which is positive to ninhydrin colorationwere united and the so-united fractions were evaporated to dryness. Theresulting product (49.6 mg) was dissolved in 2.7 ml of anhydroustetrahydrofuran and thereto were added 35 μl of acetic acid and 535 μlof 1 M tetrabutylammonium fluoride/tetrahydrofuran and the resultingmixture was agitated at room temperature for 1 hour in a tightly closedvessel. The resulting mixture was diluted with ethyl acetate, followedby washing with saturated aqueous sodium bicarbonate solution and, then,with saturated aqueous sodium chloride solution with subsequent drying,whereupon the solvent was distilled off under a reduced pressure. Bypurifying the resulting residue, by a silica gel chromatography (witheluting off low polar impurities with methanol/chloroform of 1/10 andeluting with conc. aq. ammonia/methanol/chloroform of 1/9/50), 30.5 mgof free amine product of the above-identified compound were obtained.This was converted into hydrochloride salt by a usual technique,followed by dissolution in small amount of methanol, dilution with ethylacetated, crystallization and collecting by filteration, 29.5 mg of theabove-identified compound were obtained. Rf=0.14 (methanol/chloroform of1/5).

EXAMPLE 69(R)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

In accordance with the procedures described in Example 12, theabove-identified compound (37.6 mg) was obtained from Intermediate 19(220 mg) and Intermediate 5 (121.7 mg).

Retention time: 36.3 min. for R-modification (41.7 min. forS-modification); Analytical condition: column: two sets, 4.6 mm×150 mm,CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(7/3); flow rate: 0.5ml/min.: detection: 254 nm; temperature: 40° C.

EXAMPLE 70(R)-N-[3-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

In accordance with the procedures described in Example 14, theabove-identified compound (167.0 mg) was obtained from Intermediate 26(815 mg) and Intermediate 5 (455 mg).

Retention time: 28.7 min. for R-modification (25.4 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(7/3); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 71(R)-N-[3-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamidehydrochloride

In accordance with the procedures described in Example 14, theabove-identified compound (55.5 mg) was obtained from Intermediate 26(815 mg) and Intermediate 17 (564.6 mg).

Retention time: 77.6 min. for R-modification (64.7 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(8/2); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 72(R)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

In accordance with the procedures described in Example 12, theabove-identified compound (223.2 mg) was obtained from Intermediate 19(642 mg) and Intermediate 39 (380 mg).

Retention time: 36.3 min. for R-modification (38.6 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(7/3); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 73(R)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

A. Synthesis of(R)-N'-[5-(2-bromo-1-hydroxyethyl)-2-benzyloxyphenyl]-N,N-dimethylsulfamide

In accordance with the procedures described in the synthesis ofIntermediate 19, the above-identified compound (925.7 mg) was obtainedfrom Intermediate 40 (1.058 g).

Retention time: 19.6 min. for R-modification (17.4 min. forS-modification); Analytical condition: column: 4.6 mm ID×250 mm.CHIRALCEL OJ (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (1/1); flow rate: 0.7 ml/min.; detection: 254 nm;temperature: R.T.

B. Synthesis of(R)-N'-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 94)

In the same manner as in the synthesis of Intermediate 42 (racemi), theabove-identified compound(1.27 g) was obtained from above-mentionedIntermediate (925 mg) in two process steps.

C. Synthesis of(R)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 95)

In the same manner as the synthesis of Intermediate 43, theabove-identified compound (262.2 mg) was obtained from Intermediate 94(590 mg) and Intermediate 2 (294 mg). Rf=0.54 (methanol/chloroform of1/10).

D. Synthesis of(R)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 96)

In accordance with the procedures described in Example 42, theabove-identified compound (83.7 mg) was obtained from Intermediate 95(120 mg).

E. Synthesis of(R)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

The above-identified compound (75.6 mg) was obtained by reaction andafter-treatment of Intermediate 96 (82 mg) in accordance with theprocedures described in Example 25.

Retention time: 38.0 min. for R-modification (47.7 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(7/3); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 74(S)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

A. Synthesis of(S)-N'-[5-(2-bromo-1-hydroxyethyl)-2-benzyloxyphenyl]-N,N-dimethylsulfamide

In accordance with the procedures of synthesis of Intermediate 19, theabove-identified compound (928.1 mg) was obtained from Intermediate40(1.05 g) using as the asymmetric catalyst an (S)-modification.

Retention time: (19.6 min. for R-modification) 17.4 min. forS-modification; Analytical condition: column: 4.6 mm ID×150 mm,CHIRALCEL OJ (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (1/1); flow rate: 0.7 ml/min.; detection: 254 nm;temperature: R.T.

B. Synthesis of(S)-N'-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 97)

In the same manner as in the synthesis of Intermediate 42 (racemi), theabove-identified compound (1.18 g) was obtained from above-mentionedIntermediate (868.1 mg) in two process steps.

C. Synthesis of(S)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 98)

In the same manner as the synthesis of Intermediate 43, theabove-identified compound (120.8 mg) was obtained from Intermediate 97(300 mg) and Intermediate 2 (144 mg).

D. Synthesis of(S)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 99)

In accordance with the procedures described for the synthesis of thecompound Example 42, the above-identified compound (83.7 mg) wasobtained from Intermediate 98 (120.8 mg).

E. Synthesis of(S)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

The above-identified compound (42.3 mg) was obtained by reaction andafter-treatment of Intermediate 99 (65.8 mg) in accordance with theprocedures described in Example 25.

Retention time: (38.5 min. for R-modification) 47.7 min. forS-modification; Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate:0.5 ml/min.; detection: 254 nm: temperature: 40° C.

EXAMPLE 75(R)-N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

In accordance with the procedures described in Example 73, theabove-identified compound (32.9 mg) was obtained from Intermediate 94(240 mg) and Intermediate 5 (115.4 mg).

Retention time: 18.3 min. for R-modification (21.5 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(6/4); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 76(S)-N'-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamidehydrochloride

In accordance with the procedures described in Example 74, theabove-identified compound (39.6 mg) was obtained from Intermediate 97(240 mg) and Intermediate 5 (114.4 mg).

Retention time: (18.3 min. for R-modification) 21.5 min. forS-modification; Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(6/4): flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 77(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

A. Synthesis of(R)-N-[5-(2-bromo-1-hydroxyethyl)-2-fluorophenyl]methanesulfonamide(Intermediate 100)

In accordance with the procedures described in the synthesis ofIntermediate 19, the above-identified compound (1.79 g) was obtainedfrom Intermediate 9 (1.53 g) by reaction and after-treatment.

Retention time: 31.1 min. for R-modification (33.3 min. forS-modification); Analytical condition: column: 4.6 mm ID×250 mm,CHIRALPAK AD (supplied from Daicel Chem. Ind.): mobile phase:ethanol/n-hexane (1/1): flow rate: 0.3 ml/min.; detection: 254 nm;temperature: R. T.

B. Synthesis of(R)-N-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 101)

In accordance with the procedures for synthesis of Intermediate 20,theabove-identified compound (2.29 g) was obtained from Intermediate 100(1.78 g) by reaction and after-treatment.

C. Synthesis of(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 102)

In accordance with the procedures for synthesis of Intermediate 21, theabove-identified compound (243.0 mg) was obtained from Intermediate 101(445 mg)and Intermediate 2 (294 mg) by reaction and after-treatment.Rf=0.50 (methanol/chloroform of 1/10).

D. Synthesis of(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

Intermediate 102 (243 mg) was dissolved in anhydrous tetrahydrofuran (15ml), whereto 4 N hydrogenchloride/1,4-dioxane (1 ml) was added and themixture was agitated at room temperature for 1 hour. The depositedprecipitate was taken out and washed with tetrahydrofuran, whereupon itwas dried under a reduced pressure at 40° C., whereby theabove-identified compound was obtained (96.8 mg).

Retention time: 42.1 min. for R-modification (38.5 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(7/3); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 78(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

A. Synthesis of(S)-N-[5-(2-bromo-1-hydroxyethyl)-2-fluorophenyl]methanesulfonamide(Intermediate 103)

In accordance with the procedures of synthesis of Intermediate 19, theabove-identified compound (1.36 g) was obtained from Intermediate 9(1.53 g) using as the asymmetric catalyst an (S)-modification byreaction and after-treatment.

Retention time: (31.1 min. for R-modification) 33.3 min. forS-modification; Analytical condition: column: 4.6 mm ID×250 mm,CHIRALPAK AD (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (1/1); flow rate: 0.3 ml/min.; detection: 254 nm;temperature: R.T.

B. Synthesis of(S)-N-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 104)

In accordance with the procedures for synthesis of Intermediate 20, theabove-identified compound (1.85 g) was obtained from Intermediate 103(1.36 g) by reaction and after-treatment.

C. Synthesis of(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 105)

In accordance with the procedures for synthesis of Intermediate 21, theabove-identified compound (198.2 mg) was obtained from Intermediate 104(445 mg) and Intermediate 2 (294 mg) by reaction and after-treatment.

D. Synthesis of(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamidehydrochloride

Intermediate 105 (154.8 mg) was dissolved in anhydrous tetrahydrofuran(6.8 ml), whereto 4 N hydrogenchloride/1,4-dioxane (430 μl) was addedand the mixture was agitated at room temperature for 1 hour. Thedeposited precipitate was taken out and was washed with tetrahydrofuran,whereupon it was dried under a reduced pressure at 40° C., whereby theabove-identified compound was obtained (109.0 mg).

Retention time: (42.1 min. for R-modification) 38.5 min. forS-modification; Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.): mobile phase: 0.5M NaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 79(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

A. Synthesis of(R)-N-[5-(2-bromo-1-hydroxyethyl)-2-chlorophenyl]methanesulfonamide(Intermediate 106)

In accordance with the procedures of synthesis of Intermediate 19, theabove-identified compound (880 mg) was obtained from Intermediate 13(800 mg) by reaction and after-treatment.

Retention time: 14.1 min. for R-modification (16.8 min. forS-modification); Analytical condition: column: 4.6 mm ID×250 mm,CHIRALPAK AD (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (4/1); flow rate: 0.5 ml/min.; detection: 254 nm:temperature: R.T.

B. Synthesis of(R)-N-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 107)

In accordance with the procedures for synthesis of Intermediate 20, theabove-identified compound (1.24 g) was obtained from Intermediate 106(880 mg) by reaction and after-treatment.

C. Synthesis of(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 108)

In accordance with the procedures for synthesis of Intermediate 21, theabove-identified compound (135.9 mg) was obtained from Intermediate 107(489.4 mg) and Intermediate 2 (294 mg) by reaction and after-treatment.Rf=0.57 (methanol/chloroform of 1/10).

D. Synthesis of(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

Intermediate 108 (73.2 mg) was dissolved in anhydrous tetrahydrofuran(4.2 ml), whereto 4 N hydrogenchloride/1,4-dioxane (240 g 1) was addedand the mixture was agitated at room temperature for 1 hour. Thedeposited precipitate was taken out and washed with tetrahydrofuran,whereupon it was dried under a reduced pressure at 40° C., whereby theabove-identified compound was obtained (36.3 mg).

Retention time: 61.7 min. for R-modification (58.4 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(7/3); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 80(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

A. Synthesis of(S)-N-[5-(2-bromo-1-hydroxyethyl)-2-chlorophenyl]methanesulfonamide(Intermediate 109)

In accordance with the procedures of synthesis of Intermediate 19, theabove-identified compound (753.4 mg) was obtained from Intermediate 13(780 mg) using as the asymmetric catalyst an (S)-modification byreaction and after-treatment.

Retention time: (14.1 min. for R-modification) 16.8 min. forS-modification; Analytical condition: column: 4.6 mm ID×250 mm,CHIRALPAK AD (supplied from Daicel Chem. Ind.): mobile phase:ethanol/n-hexane (4/1); flow rate: 0.5 ml/min.; detection: 254 nm:temperature: R.T.

B. Synthesis of(S)-N-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 110)

In accordance with the procedures for synthesis of Intermediate 20, theabove-identified compound (1.06 g) was obtained from Intermediate 109(753 mg) by reaction and after-treatment.

C. Synthesis of(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 111)

In accordance with the procedures for synthesis of Intermediate 21, theabove-identified compound (111.2 mg) was obtained from Intermediate 110(490 mg) and Intermediate 2 (294 mg) by reaction and after-treatment.

D. Synthesis of(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamidehydrochloride

Intermediate 111 (111.2 mg) was dissolved in anhydrous tetrahydrofuran(6.3 ml), whereto 4 N hydrogenchloride/1,4-dioxane (360 μl) was addedand the mixture was agitated at room temperature for 1 hour. Thedeposited precipitate was taken out and washed with tetrahydrofuran,whereupon it was dried under a reduced pressure at 40° C., whereby theabove-identified compound was obtained (70.4 mg).

Retention time: (61.7 min. for R-modification) 58.4 min. forS-modification; Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase: 0.5M NaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 81(R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

A. Synthesis of(R)-N-methyl-[5-(2-bromo-1-hydroxyethyl)-2-benzyloxy]benzenesulfonamide(Intermediate 112)

In accordance with the procedures of synthesis of Intermediate 19, theabove-identified compound (752.2 mg) was obtained from Intermediate 81(800 mg)by reaction and after-treatment. Rf=0.15 (ethyl acetate/n-hexaneof 1/2).

B. Synthesis of(R)-N-methyl-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-benzyloxy]benzenesulfonamide(Intermediate 113)

In accordance with the procedures for synthesis of Intermediate 20, theabove-identified compound (587.9 mg) was obtained from Intermediate 112(462.8 mg) by reaction and after-treatment. Rf=0.53 (ethylacetate/n-hexane of 1/2).

C. Synthesis of(R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-benzyloxy]benzenesulfonamide(Intermediate 114)

In accordance with the procedures for synthesis of Intermediate 21, theabove-identified compound (265.3 mg) was obtained from Intermediate 113(587.9 mg) and Intermediate 2 (295 mg) by reaction and after-treatment.Rf=0.45 (methanol/chloroform of 1/10).

D. Synthesis of(R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamide(Intermediate 115)

To a solution of Intermediate 114 (265.3 mg) in 13.3 ml of anhydroustetrahydrofuran, acetic acid (169.6 μl) and 1 M solution (2.65 ml) oftetrabutylammonium fluoride in tetrahydrofuran were added and themixture was agitated at room temperature for 1 hour. The reactionmixture was diluted with ethyl acetate and was washed with saturatedaqueous sodium bicarbonate solution and then with saturated aqueoussodium chloride solution, followed by drying over anhydrous sodiumsulfate, whereupon the solvent was distilled off under a reducedpressure. The resulting residue was triturated in ethanol, whereupon theabove-identified compound (111.3 mg) was obtained. On the other hand,the residue left after evaporation of the filtrate was purified by asilica gel chromatography (methanol/chloroform of 7/100), whereby theabove-identified compound was obtained (59 mg).

E. Synthesis of(R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

In accordance with the procedure described in Example 2, Intermediate115 (166.3 mg) was treated by reaction and after-treatment, whereby theabove-identified compound (136.3 mg) was obtained.

Retention time: 117.8 min. for R-modification(132.6 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase: 0.5M NaClO₄ /HClO₄ buffer solution (pH 2.0)/acetonitrile(78/22); flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 82(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]methanesulfonamidehydrochloride

A. Synthesis of 1-(4-acetylamino-3-nitrophenyl)ethanone (Intermediate116)

To 4.5 ml of ice-cooled acetic anhydride, 0.5 ml of fuming nitric acidwas added in five allotted portions under agitation. Thereto were addeddropwise a solution of 350 mg of 4-acetamid-acetophenone (supplied fromthe firm Lancaster) in acetic acid (1.8 ml) over a period of 7 minutes,while maintaining the temperature below 12° C. After agitation for 38minutes at 5° C., 10 ml of water and 10 ml of ethyl acetate were addedthereto and the organic layer was separated. The aqueous layer wassubjected extraction with 10 ml of ethyl acetate and the organic layerswere united and the united organic phase was poured into 200 ml ofsaturated aqueous sodium bicarbonate solution and the mixture wasagitated for 30 minutes. The organic layer was separated and the aqueouslayer was subjected to extraction with 50 ml of ethyl acetate and theorganic layers were brought together and the so-united organic phase wasdried, followed by distilling off of the solvent, whereby 0.41 g of theabove-identified compound was obtained. Rf=0.67 (methanol/chloroform of1/19).

B. Synthesis of 1-(3-amino-4-acetylaminophenyl)ethanone (Intermediate117)

To a solution of 410 mg of Intermediate 116 in 40 ml of methanol, 20 mgof platinum oxide were added under argon atmosphere and the reactionsystem was replaced with hydrogen gas under ice-cooling. The mixture wasagitated at room temperature for 12.5 hours, whereupon the reactionsystem was replaced with argon gas and 20 ml of chloroform wereintroduced into the reaction mixture. Catalyst was separated and thesolvent in the filtrate was distilled off under a reduced pressure. Theresulting residue was purified by a silica gel chromatography (elutedwith ethyl acetate/n-hexane of 3/7--solely with ethyl acetate), whereby0.29 g of the above-identified compound was obtained. Rf=0.06(methanol/chloroform of 1/19).

C. Synthesis of1-[4-acetylamino-3-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate118)

According to the method reported by A. A. Larsen et al in J. Med. Chem.,10, 462-472 (1967), the above-identified compound was prepared fromIntermediate 117 (290 mg) and methanesulfonyl chloride (118.5 μl).Here,however, a modification in the purification of the reaction mixturewas incorporated such that the reaction was terminated with addition of10 ml of water with adjustment of pH at 4 by 1 N hydrochloric acid,before extraction with ethyl acetate (4 times each with 30 ml). Theorganic layer was washed with saturated aqueous sodium chloride solutionand dried, whereupon the solvent was distilled off under a reducedpressure. By purifying the resulting residue by a silica gelchromatography (methanol/chloroform of 3/97), 315 mg of theabove-identified compound were obtained. Rf=0.37 (methanol/chloroform of1/19).

D. Synthesis of2-bromo-1-[4-acetylamino-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 119)

In the same manner as the procedures described in the step A of Example29 except that the purification of the compound from the reactionmixture was performed only by a silica gel chromatography (elution withethyl acetate/n-hexane of 7/13--with ethyl acetate only), 267 mg of theabove-identified compound were obtained from 310 mg of Intermediate 118and 570 mg of cupric bromide. Rf=0.68 (ethyl acetate/n-hexane of 1/1).

E. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-acetylaminophenyl]methanesulfonamide(Intermediate 120)

In the same manner as the procedures described in the step D of Example1 except that only a silica gel chromatography (methanol/chloroform of5/95-15/85) was employed for purifying the crude product, theabove-identified compound (53 mg) was synthesized from Intermediate 119(147 mg) and Intermediate 2 (90.5 mg). Rf=0.17 (methanol/chloroform of1/9).

F. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]methanesulfonamidehydrochloride

70 mg of Intermediate 120 were added to 8 ml of 1,4-dioxane and theretowere added 2 ml of concentrated hydrochloric acid, whereupon to reactionmixture was agitated for 1 hour with heating under reflux. The mixturewas evaporated to dryness under a reduced pressure and the resultingresidue (60 mg ) was processed by recrystallization from methanol/ethylacetate, whereby 13 mg of the above-identified compound were obtained.Rf=0.05 (water/methanol/chloroform of 1/15/25).

EXAMPLE 83(±)-N-methyl-N-benzyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

A. Synthesis ofN-methyl-N-benzyl-(2-benzyloxy-5-acetyl)benzenesulfonamide (Intermediate121)

In the same manner as the procedures described in the step A of Example65, the above-identified compound was prepared from1-(3-amino-4-benzyloxy-phenyl)ethanone. Here, however, instead of adding40% aqueous solution of methylamine, 0.2 ml of N-methyl-benzylamine and0.7 ml of triethylamine were reacted in 10 ml of dichloromethane for31.5 hours. To the reaction mixture, 10 ml of water were added and theorganic layer was collected. The organic layer was washed with 1 Nhydrochloric acid and saturated aqueous sodium chloride solution,followed by drying, whereupon the solvent was distilled off under areduced pressure, whereby 398 mg of the above-identified compound wereobtained. Rf=0.36 (ethyl acetate/n-hexane of 1/2).

B. Synthesis ofN-methyl-N-benzyl-[2-benzyloxy-5-(2-bromoacetyl)]benzenesulfonamide(Intermediate 122)

In the same manner as the procedures described in the step A of Example29 except that the purification was effected by a silica gelchromatography (ethyl acetate/n-hexane of 1/9-1/4), the above-identifiedcompound (228 mg) was produced from Intermediate 121 (205 mg) and cupricbromide (246 mg). Rf=0.50 (ethyl acetate/n-hexane of 1/2).

C. Synthesis of(±)-N-methyl-N-benzyl-[5-[2-[2-(9H-carbnazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamide(Intermediate 123)

According to the procedures described in the step D of Example 1 exceptthat a silica gel chromatography (elution with methanol/chloroform of5/95 for the first and with methanol/ethyl acetate of 1/19 for thesecond elution) was employed for the purification of crude product, theabove-identified compound (0.20 g ) was obtained from Intermediate 122(228 mg) and Intermediate 2 (102 mg). Rf=0.25(methanol/chloroform of1/19).

D. Synthesis of(±)-N-methyl-N-benzyl-[5-[2-(2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

According to the procedures described in Example 2, 0.20 g ofIntermediate 123 were subjected to a hydrogenolysis for 1 hour using 100mg of 10% palladium/carbon black, followed by conversion intohydrochloride salt and recrystallization from methanol/ethyl acetate,whereby 62 mg of the above-identified compound were obtained. Rf=0.31(methanol/chloroform of 1/9).

EXAMPLE 84(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenyl]methanesulfonamide

A. Synthesis of 1-[4-(ethoxycarbonyl)phenyl]ethanoneethyleneacetal(Intermediate 124)

9.61 g of 4-acetylbenzoic acid ethyl ester (supplied from the firm WakoPure Chem. Ind.) were dissolved in 200 ml of toluene and thereto wereadded 20 ml of ethylene glycol and 200 mg of p-toluenesulfonic acidhydrate under argon atmosphere, whereupon the mixture was heated underreflux for 24 hours on Dean-Stark apparatus while removing water. Thereaction mixture was then cooled down to room temperature and thetoluene layer was washed with water (twice with each 100 ml) and, then,with saturated aqueous sodium chloride solution (100 ml), followed bydrying and evaporation to dryness under a reduced pressure, whereby theabove-identified compound (12.76 g ) was obtained. Rf=0.58 (ethylacetate/n-hexane of 1/2).

B. Synthesis of 1-[4-(hydroxymethyl)phenyl]ethanone (Intermediate 125)

1.90 g of lithium aluminum hydride were suspended in 120 ml of anhydroustetrahydrofuran under argon atmosphere and thereto were added dropwise asolution of 12.76 g of Intermediate 124 in 40 ml of anhydroustetrahydrofuran over a period of 90 minutes under ice-cooling withsubsequent agitation for 90 minutes. Thereto were added 100 ml of ethylacetate gradually over a period of 25 minutes to terminate the reaction,whereupon 100 ml of 1 N sulfuric acid were added thereto over a periodof 30 minutes. The mixture was further agitated at room temperature for45 minutes, whereupon 100 ml of water were added thereto and the organicphase was collected. The aqueous phase was subjected to extraction withethyl acetate (twice with each 100 ml) and the organic layers werebrought together and the so-united organic phase was washed with water(100 ml) and, then, with saturated aqueous sodium chloride solution (100ml), followed by drying and distilling off of the solvent under areduced pressure. The resulting residue (12.25 g) was dissolved inacetone (200 ml), whereto p-toluenesulfonic acid hydrate (200 mg) wasadded and the mixture was agitated for 20 hours at room temperature,After confirmation of termination of the reaction by ¹ H-NMR, theacetone solvent was distilled off under a reduced pressure. The residuewas treated by partition between 50 ml of ethyl acetate and 50 ml ofwater and the organic layer was separated, which was washed withsaturated aqueous sodium chloride solution and dried, before the solventwas distilled off under a reduced pressure, whereby 6.688 g of theabove-identified compound were obtained. Rf=0.19 (ethyl acetate/n-hexaneof 1/2).

C. Synthesis of 1-[4-(acetoxymethyl)phenyl]ethanone (Intermediate 126)

6.67 g of Intermediate 125 were dissolved in 7.3 ml of pyridine andthereto were added 6.3 ml of acetic anhydride, whereupon the mixture wasagitated at room temperature for 12.5 hours. Thereto were added 300 mlof water to terminate the reaction and the mixture was subjected toextraction with 50 ml of ethyl acetate. The aqueous layer was treated byextraction with ethyl acetate (twice with each 50 ml) and the organiclayers were brought together, whereupon the so-united organic phase waswashed with 100 ml of water, 50 ml of 1 N hydrochloric acid and,finally, 50 ml of saturated aqueous sodium chloride solution,successively, followed by drying and evaporation of the solvent under areduced pressure, whereby 8.27 g of the above-identified compound wereobtained. Rf=0.56 (ethyl acetate/n-hexane of 1/1).

D. Synthesis of 1-[3-nitro-4-(acetoxymethyl)phenyl]ethanone(Intermediate 127)

To 80 ml of fuming nitric acid under cooling with an ice/salt coolant,8.09 g of Intermediate 126 were added all at once. While maintainingthis temperature, the mixture was agitated for 10 minutes, before it waspoured into 300 ml of ice/water mixture. This was treated by extractionwith ethyl acetate (three times with each 80 ml) and the organic layerwas washed with water (three times with each 100 ml), with saturatedaqueous sodium bicarbonate solution and with saturated aqueous sodiumchloride solution, successively, with subsequent drying, whereupon thesolvent was distilled off under a reduced pressure. The resultingresidue (9.70 g) was purified by a silica gel chromatography (ethylacetate/n-hexane of 1/2), whereby 8.41 g of the above-identifiedcompound were obtained. Rf=0.36 (ethyl acetate/n-hexane of 1/2).

E. Synthesis of 1-[3-amino-4-(acetoxymethyl)phenyl]ethanone(Intermediate 128)

1.97 g of Intermediate 127 were dissolved in 358 ml of methanol andthereto were added 10.55 g of stannous chloride and 7.5 ml ofconcentrated hydrochloric acid under argon atmosphere, whereupon themixture was agitated at room temperature for 2 hours. Thereto were added200 ml of saturated aqueous sodium bicarbonate solution and the mixturewas agitated at room temperature for 75 minutes, whereupon the inorganicsalts precipitated were removed by filtering on celite and the filtratewas evaporated under a reduced pressure to a volume of about 200 ml.This was subjected to extraction with ethyl acetate (300 ml) and theextract was washed with saturated aqueous sodium chloride solution withsubsequent drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue (1.32 g) was purified by asilica gel chromatography (ethyl acetate/n-hexane of 1/2), whereby 0.56g of the above-identified compound was obtained. Rf=0.31 (ethylacetate/n-hexane of 1/2).

F. Synthesis of1-[3-(methylsulfonyl)amino-4-(acetoxymethyl)phenyl]ethanone(Intermediate 129)

0.56 g of Intermediate 128 was dissolved in 3.6 ml of pyridine andthereto were added 215 μl of methanesulfonyl chloride under argonatmosphere and the mixture was agitated at room temperature for 26hours. Thereto were added 5 ml of water and the mixture was subjected toextraction with ethyl acetate (three times with each 20 ml) and theorganic layer was washed with 1 N hydrochloric acid (twice with each 50ml) and saturated aqueous sodium chloride solution, successively, withsubsequent drying, whereupon the solvent was distilled off under areduced pressure, whereby 0.58 g of the above-identified compound wasobtained. Rf=0.39 (ethyl acetate/n-hexane of 1/1).

G. Synthesis of2-bromo-1-[3-(methylsulfonyl)amino-4-(acetoxymethyl)phenyl]ethanone(Intermediate 130)

In the same manner as the procedures described in the step A of Example29, the above-identified compound (430 mg) was produced fromIntermediate 129 (285 mg) and cupric bromide (491 mg, supplied fromKanto Chem. Co., Inc.). Rf=0.44 (ethyl acetate/n-hexane of 1/2).

H. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(acetoxymethyl)phenyl]methanesulfonamide(Intermediate 131)

According to the procedures described in the step D of Example 1 exceptthat a silica gel chromatography (with methanol/ethyl acetate of 1/9-1/4for the first and with 10% conc. aq. ammonia-containingmethanol/chloroform of 2/25 for the second) was employed for thepurification of the crude product, the above-identified compound (68 mg)was obtained from Intermediate 130 (405 mg) and Intermediate 2 (226mg).Rf=0.18(10% conc. aq. ammonia-containing methanol/chloroform of 1/9).

I. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenyl]methanesulfonamidehydrochloride

To 68 mg of Intermediate 131, 10 ml of 2 N aqueous sodium hydroxidesolution were added and the mixture was agitated at room temperature for2.5 hours. This was diluted with 30 ml of water and thereto were added50 ml of saturated aqueous sodium chloride solution, followed byextraction with ethyl acetate(three times with each 50 ml). The organiclayer was dried and the solvent was distilled off therefrom under areduced pressure, whereupon the resulting residue was purified by asilica gel chromatography (10% conc. aq. ammonia-containingmethanol/ethyl acetate of 1/9), whereby free base product of theabove-identified compound was obtained. This was converted intohydrochloride salt by a usual technique, which was then treated bycrystallization from methanol/ethyl acetate to obtain 22 mg of theabove-identified compound. Rf=0.11 (10% conc. aq. ammonia-containingmethanol/chloroform of 1/9).

EXAMPLE 85(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide

2-bromo-1-[4-bromo-3-[(methylsulfonyl)amino]phenyl]ethanone was producedin the same manner as in the steps B, C and D of Example 6 in accordancewith the procedures for the synthesis of Intermediate 13.

A. Synthesis of 1-(3-amino-4-bromophenyl)ethanone

To a solution of 5.0 g of 4-bromo-3-nitroacetophenone (supplied from thefirm Lancaster) in 890 ml of methanol, 19.4 g of tin (II) chloride and17 ml of concentrated hydrochloric acid were added and the mixture wasagitated at room temperature for 3.5 hours. There to were added 470 mlof saturated aqueous sodium bicarbonate solution and the depositedprecipitate was filtered off,which was subjected to extraction withethyl acetate. The organic layer was dried and concentrated under areduced pressure, whereby 3.97 g of the above-identified compound wereobtained. Rf=0.43 (ethyl acetate/n-hexane of 1/2).

B. Synthesis of 1-[4-bromo-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 132)

To a solution of 3.97 g of the above compound in 21 ml of pyridine, 1.8ml of methanesulfonyl chloride were added at room temperature and themixture was agitated for 1 hour. The mixture was poured into 142 ml ofwater. After agitation overnight, the deposited precipitate was isolatedby filtration and was dissolved in ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride solution with subsequentdrying, and concentrated under a reduced pressure to obtain a crudeproduct (4.08 g). Rf=0.41 (ethyl acetate/n-hexane of 1/1).

C. Synthesis of2-bromo-1-[4-bromo-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 133)

To a solution of 4.08 g of Intermediate 132 in 40 ml of 1,4-dioxane,0.75 ml of bromine was added with agitation under argon atmosphere. Theresulting mixture was warmed to 60° C. and was agitated for 1.5 hours.After having been cooled to room temperature, water was added. Themixture was extracted with ethyl acetate, organic layer was washed withsaturated aqueous sodium chloride solution and dried. The mixture wasconcentrated under a reduced pressure to obtain a crude product (6.28g). To this, a 1/1 liquid mixture of ethyl acetate/n-hexane was addedand warmed and cooled and the deposited precipitate was isolated byfiltration, whereby 4.0 g of the above-identified compound wereobtained. Rf=0.54 (ethyl acetate/n-hexane of 1/1).

D. Synthesis of(±)-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamidehydrochloride

According to the procedures described in the step D of Example 1, a freeamine product of the above-identified compound (191,6 mg) was producedfrom HBr-addition salt of Intermediate 2 (452.5 mg) and Intermediate 133(742.1 mg) through reaction and after-treatment with subsequentpurification by a PTLC (with development by methanol/chloroform of1/10). Rf=0.58 (methanol/ethyl acetate of 1/3).

This was converted into its hydrochloride salt (the above-identifiedcompound) by adding thereto 1.1 equivalent amount of 0.1 N hydrogenchloride/ethanol, wherefrom the solvent was distilled off under areduced pressure. To the resulting residue, diethyl ether was added andthe deposited precipitate was collected by filtration and was processedby recrystallization from ethanol, followed by drying at 50° C. under areduced pressure, whereby the above-identified compound(112.6 mg) wasobtained as a powdery product.

EXAMPLE 86(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-iodophenyl]methanesulfonamide

2-bromo-1-[4-iodo-3-[(methylsulfonyl)amino]phenyl]ethanone was producedin the same manner as in the steps A, B, C and D of Example 6.

A. Synthesis of 1-(4-iodo-3-nitrophenyl)ethanone (Intermediate 134)

20 g of 4'-iodoacetophenone (Tokyo Chemical Industry Co., Ltd.) wereadded in two portions to 130 ml of fuming nitric acid cooled withice/salt. After agitation for 15 minutes, the resulting mixture waspoured into 1 liter of ice water and was then subjected to extractionwith 1 liter of ethyl acetate. The organic layer was separated and driedand the solvent was evaporated off, whereby 20.7 g of theabove-identified compound were obtained. Rf=0.19 (ethyl acetate/n-hexaneof 1/5).

B. Synthesis of 1-(3-amino-4-iodophenyl)ethanone (Intermediate 135)

To a solution of 14.3 g of Intermediate 134 in 2134 ml of methanol, 40.5g of tin (II) chloride and 40.8 ml of concentrated hydrochloric acidwere added and the mixture was agitated at room temperature for 4.75hours. To this mixture, 1100 ml of saturated aqueous sodium bicarbonatesolution were added and deposited precipitate was separated byfiltration. Filtrate was partly concentrated and was subjected toextraction with ethyl acetate. The organic layer was dried andconcentrated to dryness under a reduced pressure, whereby 11.87 g of theabove-identified compound were obtained. Rf=0.67 (methanol/chloroform of1/10).

C. Synthesis of 1-[4-iodo-3-[(methylsulfonyl)amino]phenyl]ethanone(Intermediate 136)

To a solution of 11.87 g of the Intermediate 135 in 50 ml of pyridine,3.55 ml of methanesulfonyl chloride were added at room temperature.After agitation for 2.5 hours, the reaction mixture was poured intowater (250 ml). The deposited precipitate was separated by filtrationand dissolved in ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride solution and dehydrated andconcentrated under a reduced pressure to obtain a crude product. Tothis, ethyl acetate/n-hexane (1/1) was added and deposited precipitatewas recovered by filtration and drying, whereby 10.44 g theabove-identified compound were obtained. Rf=0.14 (ethyl acetate/n-hexaneof 1/3).

D. Synthesis of2-bromo-1-[4-iodo-3-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate137)

To a solution of 10.4 g of Intermediate 136 in 102 ml of 1,4-dioxane,1.66 ml of bromine were added under argon atmosphere with agitation. Theresulting mixture was warmed to 60° C. and was agitated for 1.5 hours.After having been cooled to room temperature, it was processed byextraction of water and ethyl acetate, washing of the organic layer,drying and evaporating under reduced pressure, whereby 11.77 g of theabove-identified compound were obtained. Rf=0.25 (ethyl acetate/n-hexaneof 1/2).

E. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-iodophenyl]methanesulfonamidehydrochloride

According to the procedures described in the step D of Example 1, freeamine product of the above-identified compound (211.5 mg) was obtainedfrom Intermediate 2 (500 mg) and Intermediate 137 (1.385 g) by reactionand after-treatment through crude purification of the resulting residueon a column chromatography (6.3% methanol/chloroform) and finepurification by a PTLC (development with 10% conc. aq.ammonia-containing methanol/ethyl acetate of 1/4). Rf=0.49 (10% conc.aq. ammonia-containing methanol/ethylacetate of 1/4).

To this product, 1.1 equivalent amount of 0.1 N hydrochloricacid/ethanol were added to convert it into hydrochloride salt (theabove-identified compound) and the solvent was distilled off under areduced pressure. After drying at 50° C. under reduced pressure 218 mgof the above-identified compound were obtained as a powdery product.

EXAMPLE 87(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N-methyl-N-benzylsulfamidehydrochloride

A. Synthesis of N-methyl-N-benzylsulfamoyl chloride

To an ice-cooled solution of 3.0 ml of sulfurylchloride in 50 ml ofdichloromethane under argon atmosphere, 6.45 ml of N-methy-N-benzylamine and 7.0 ml of triethylamine were added over a period of 15minutes. After agitation for 15 minutes, 50 ml of water was addedthereto to terminate the reaction. The organic layer was separated andwashed with 50 ml of 1 N hydrochloric acid with subsequent drying,whereupon the solvent was distilled off under a reduced pressure. 100 mlof n-hexane were added to the resulting residue (8.35 g) and the mixturewas cooled, whereupon the deposited precipitate was filtered off. Thefiltrate was evaporated to dryness under a reduced pressure, whereby5.30 g of the above-identified compound were obtained. Rf=0.64 (ethylacetate/n-hexane of 1/4).

B. Synthesis of1-[4-benzyloxy-3-[(N-methyl-N-benzylsulfamoyl)amino]phenyl]ethanone(Intermediate 138)

The above-identified compound (671 mg) was produced from the aboveIntermediate (880 mg) and 1-(3-amino-4-benzyloxyphenyl)ethanone (482 mg)[this was carried out in accordance with the method reported by A. A.Larsen et al in J. Med. Chem., 10, 462-472(1967)]. Here, however, amixed solvent of pyridine/dichloromethane (7 ml, 2/5) was used and thereaction mixture was agitated first at room temperature for 66 hours and,then, agitated with heating under reflux for further 2 hours. Thepurification was performed by extraction with 20 ml of water and 50 mlof ethyl acetate and washing the organic layer with 30 ml of 1 Nhydrochloric acid. The united aqueous phase was extracted further withethyl acetate (twice with each 30 ml), whereupon the united organicphase was washed with saturated aqueous sodium chloride solution withsubsequent drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue was purified by a silica gelchromatography (ethyl acetate/n-hexane of 1/3). Rf=0.47(methanol/chloroform of 1/19).

C. Synthesis of2-bromo-1-[4-benzyloxy-3-[(N-methyl-N-benzylsulfamoyl)amino]phenyl]ethanone(Intermediate 139)

In the same manner as the procedures described in the step A of Example29, the above-identified compound (810 mg, ca. 80% purity) was producedfrom Intermediate 138 (670 mg) and cupric bromide (780 mg). Rf=0.41(ethyl acetate/n-hexane of 1/2).

D. Synthesis of(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N-methyl-N-benzylsulfamide(Intermediate 140)

The above-identified compound (251 mg) was produced through reaction andafter-treatment in accordance with the procedures described in the stepD of Example 1 from Intermediate 2 (400 mg), triethylamine (280 μl) andIntermediate 139 (805 mg) via purification by a silica gelchromatography (elution with methanol/ethyl acetate of 1/9). Rf=0.47(methanol/chloroform of 1/9).

E. Synthesis of(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N-methyl-N-benzylsulfamidehydrochloride

The above-identified compound (46 mg) was produced in accordance withthe procedures described in Example 2, by adding 250 mg of Intermediate140 to 50 ml of methanol and effecting a hydrogenolysis using 122 mg of10% palladium/carbon black with subsequent conversion into hydrochloridesalt by a usual method and recrystallization from methanol/ethylacetate. Rf=0.33 (methanol/chloroform of 1/9).

EXAMPLE 88(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-diethylsulfamidehydrochloride

A. Synthesis of N,N-diethylsulfamoyl chloride

In accordance with the procedures described in the step A of Example 87,2.07 ml of N,N-diethylamine and 2.8 ml of triethylamine were added to anice-cooled solution of 1.6 ml of sulfuryl chloride in 20 ml ofdichloromethane, over a period of 2 hours under argon atmosphere. Afteragitation for 1 hour, 20 ml of water was added thereto to terminate thereaction. The organic layer was separated and washed with 20 ml of 1 Nhydrochloric acid with subsequent drying, whereupon the solvent wasdistilled off under a reduced pressure. 30 ml of n-hexane were added tothe resulting residue and the mixture was cooled, whereupon thedeposited precipitate was filtered off. The filtrate was evaporated todryness under a reduced pressure, whereby 2.19 g of the above-identifiedcompound were obtained. Rf=0.59 (ethyl acetate/n-hexane of 1/4).

B. Synthesis of1-[4-benzyloxy-3-[(N,N-diethylsulfamoyl)amino]phenyl]ethanone(intermediate 141)

The above-identified compound (513 mg) was produced from the aboveIntermediate (686 mg) and 1-(3-amino-4-benzyloxyphenyl)ethanone (482 mg)[this was carried out in accordance with the method reported by A. A.Larsen et al in J. Med. Chem., 10, 462-472(1967)]. Here, however, amixed solvent of pyridine/dichloromethane (7 ml, 2/5) was used and thereaction mixture was agitated first at room temperature for 66 hoursand, then, agitated with heating under reflux for further 2 hours. Thepurification was performed by extraction with 20 ml of water and 20 mlof ethyl acetate and washing the organic layer with 30 ml of 1 Nhydrochloric acid. The united aqueous phase was extracted further withethyl acetate (twice with each 30 ml), whereupon the united organicphase was washed with saturated aqueous sodium chloride solution withsubsequent drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue was purified by a silica gelchromatography (ethyl acetate/n-hexane of 1/3). Rf=0.42 (ethylacetate/n-hexane of 1/2).

C. Synthesis of2-bromo-1-[4-benzyloxy-3-[(N,N-diethylsulfamoyl)amino]phenyl]ethanone(Intermediate 142)

In the same manner as the procedures described in the step A of Example29, the above-identified compound (693 mg, ca. 70% purity) was producedfrom Intermediate 141 (500 mg) and cupric bromide (670 mg). Rf=0.64(ethyl acetate/n-hexane of 1/2).

D. Synthesis of(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N,N-diethylsulfamide(Intermediate 143)

The above-identified compound (256 mg) was produced through reaction andafter-treatment in accordance with the procedures described in the stepD of Example 1 from Intermediate 2 (390 mg), triethylamine (280 μl) andIntermediate 142 (673 mg) via purification by a silica gelchromatography (elution with methanol/ethyl acetate of 1/9). Rf=0.46(methanol/chloroform of 1/9).

E. Synthesis of(±)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-diethylsulfamidehydrochloride

The above-identified compound (85 mg) was produced in accordance withthe procedures described in Example 2, by adding 250 mg of Intermediate143 to 50 ml of methanol and effecting a hydrogenolysis using 120 mg of10% palladium/carbon black with subsequent conversion into hydrochloridesalt by a usual method and recrystallization from methanol/ethylacetate. Rf=0.32 (methanol/chloroform of 1/9).

EXAMPLE 89(±)-N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

A. Synthesis ofN,N-dimethyl-[2-benzyloxy-5-(2-bromoacetyl)benzene]sulfonamide(Intermediate 144)

In the same manner as the procedures described in the steps A and B ofExample 83, the above-identified compound (705 mg) was prepared from1-(3-amino-4-benzyloxyphenyl)ethanone [prepared by the method reportedby A. A. Larsen et al in J. Med. Chem., 10, 462-472 (1967)]. Here,however,instead of adding N-methylbenzylamine, N,N-dimethylamine wasreacted. Rf=0.33 (ethyl acetate/n-hexane of 1/2).

B. Synthesis ofN,N-dimethyl-[2-benzyloxy-5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]]benzenesulfonamide(Intermediate 145)

In the same manner as the procedures for the synthesis of Intermediate42, 700 mg of Intermediate 144 were treated by reaction andafter-treatment, whereby 407 mg of the above-identified compound wereobtained. Rf=0.74 (ethyl acetate/n-hexane of 1/1).

C. Synthesis of(±)-N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-benzyloxy]benzenesulfonamide(Intermediate 146)

According to the procedures for the synthesis of Intermediate 43 exceptthat a silica gel chromatography (elution with methanol/chloroform of1/25) was employed for the purification of crude product, theabove-identified compound (138 mg ) was obtained from Intermediate 145(398 mg) and Intermediate 2 (193 mg). Rf=0.43(methanol/chloroform of1/10).

D. Synthesis of(±)-N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamide(Intermediate 147)

135 mg of Intermediate 146 were dissolved in 7 ml of anhydroustetrahydrofuran, whereto 38.2 μl of acetic acid and 314 μl of 1 Msolution of tetrabutylammonium fluoride/tetrahydrofuran were added andthe mixture was agitated at room temperature for 14.5 hours. Then, themixture was diluted with ethyl acetate, followed by rinsing withsaturated aqueous sodium chloride solution and dried,whereupon thesolvent was distilled off under a reduced pressure. The residue waspurified by a PTLC (development with methanol/chloroform of 1/10).whereby 4.9 mg of the above-identified compound were obtained. Rf=0.23(methanol/chloroform of 1/10). By a usual technique, it was convertedinto hydrochloride salt (7.7 mg).

E. Synthesis of(±)-N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamidehydrochloride

The above-identified compound (5.0 mg) was produced in accordance withthe procedures described in Example 2. by performing a hydrogenolysis ofIntermediate 147 (7.7 mg) using of 10% palladium/carbon black(4 mg) for2 hours, followed by filtering off the catalyst and distilling off thesolvent under a reduced pressure. Rf=0.31 (methanol/chloroform of 1/9).

EXAMPLE 90(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

A. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-benzyloxyphenyl]methanesulfonamide(Intermediate 148)

120 mg of the compound of Example 1 were agitated with heating underreflux in 10 ml of 10% hydrogen chloride/methanol for 24 hours. Then,the mixture was further agitated for 3 days at room temperature. Thereaction mixture was evaporated to dryness under a reduced pressure,whereto saturated aqueous sodium bicarbonate solution was added andextraction with ethyl acetate was performed (twice with each 20 ml).After drying, evaporation was carried out and the residue was purifiedby a silica gel chromatography (methanol/chloroform of 1/19), whereby 72mg of the above-identified compound were obtained. Rf=0.55(methanol/chloroform of 1/9).

B. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

In accordance with the procedures described in Example 2, 70 mg ofIntermediate 148 were subjected to hydrogenolysis using 30 mg of 10%palladium/carbon black for 1 hour, whereupon conversion intohydrochloride salt was effected with subsequent evaporation to dryness and trituration from diethyl ether, whereby 60 mg of the above-identifiedcompound were obtained. Rf=0.40 (methanol/chloroform of 1/9).

EXAMPLE 91(±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

28 mg of the compound of Example 38 were suspended in 3 ml of 10%hydrogen chloride/methanol and the mixture was agitated for 3 days withheating under reflux. Then, 10 ml of 10% hydrogen chloride/methanol werereplenished thereto and the mixture was further agitated for 2 days. Thereaction mixture was evaporated to dryness under a reduced pressure andthe residue was dissolved in methanol and purified by a PTLC(development with methanol/chloroform of 1/10). From this, bytriturating in diethyl ether and filtration, 11.8 mg of theabove-identified compound were obtained. Rf=0.38 (methanol/chloroform of1/10).

EXAMPLE 92(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-aminophenyl]methanesulfonamidehydrochloride

Intermediate 120 (35 mg) was added to 10% hydrogen chloride/methanol (5ml) and the mixture was agitated for 2 hours with heating under reflux.By evaporating to dryness, the above-identified compound (37 mg) wasobtained. Rf=0.29 (methanol/chloroform of 1/9).

Test Example 1

Human β3-agonist Activity

Human β3-agonist activity was examined using CHO cells (chinese hamsterovarian cells) to which pcDNA3 (in vitrogen) cells inserted human β3gene was transfected. Human β3 fragment was obtained by PCR using humanfat tissue cDNA (supplied from Clontech) with a β3 primer [Krief et al,J. Clin. Invest., Vol.91, p344-349 (1993)], And then full length ofhuman β3 gene was cloned using this fragment as a probe.

The cells were cultured in a HAM F-12 medium containing 10% of fetalbovine serum, 400 μg/ml of Geneticin (Gibco BRL), 100 U/ml penicillinand 10 μg/ml streptomycin. 5×10⁵ cells were placed on a 6-well plate andcultured for 24 hours, after which the medium was changed to a HAM F-12medium without serum and was kept for 2 hours. Each test compound wasfirst dissolved in DMSO, and then diluted with a HAM F-12 mediumcontaining 1 mM isobutylmethyl xanthine and 1 mM ascorbic acid. A10-fold dilution in the range of 10⁻⁵ to 10⁻¹² M was added into thecell.

After culturing for 30 minutes, culture medium was withdrawn, 0.5 ml of1 N NaOH was added and was kept for 20 minutes. And then 0.5 ml of 1 Nacetic acid was added with subsequent agitation and centrifugation.Finally the concentration of cAMP were analyzed using cAMP EIA KIT(Cayman). Intrinsic activities and ED₅₀ of 65 compounds in Example 1-92are shown in Table 2. BRL37344 was synthesized by the method given in"Drugs of the future", Vol. 16, p 797-800 (1991). CL316, 243 wassynthesized by the method given in J. Med. Che., Vol. 35, p 3081-3084.Isoprotelenol was purchased from Research Biochimicals International. Asseen in Table 2, the activities of these compounds were found to behigher than BRL 37344 and CL316,243.

Test Example 2

Effect on Heart

The hearts of male guinea pigs having body weights in the range of180-250 g were excised and each right atrium specimen was prepared whichwas set in an organ bath filled with aerated Krebs solution. Theautomaticity was measured using an isometric transducer (TB-611T of thefirm Nippon Koden) connected to a polygraph (MR-6000 of the firm NipponKoden). The ED₅₀ values for the inventive compounds in Examples werehigher than that of β3 and these compounds have almost no contributionto increase in the cardiac rate, so that they are selective and areexpected to have lower side effects.

Test Example 3

Lipolytic Activity in Canine Fatty Cell

Adipose tissues in the omentum were collected from dogs and minced andwashed. Krebs-Ringer buffer solution containing 1 mg/ml Collagenase(Sigma) and 1% of bovine serum albumin was added in an amount of 3 mlper one gram of the tissue. These cells were then incubated at 37° C.for 30 minutes with shaking and then undigested tissues were removedwith a nylon filter. The resulting adipocytes were washed four timeswith Krebs-Ringer buffer, and then the concentration of cells wasdiluted to 2×10⁵ /ml with Krebs-Ringer buffer solution containing 4% ofbovine serum albumin. These cells were transfered to Eppendorf tubeseach in an amount of 300 μl.

Each 300 μl of a culture medium containing the test compounds were addedto these tubes and was held at 37° C. for 1 hour with shaking.Stimulation was stoped by cooling with ice. After centrifugation, theadipocytes were taken off with an aspirator, whereupon the glycerol wasdetermined using F-KIT GLTCEROL (Behringer-Manheim). A shown in Table 3,the compounds of inventive Examples exhibited in vitro lipolyticactivities and, therefore, it was expected that they may be effectivealso in vivo lipolysis.

Test Example 4

Blood Sugar decreasing Effect and Lipolytic Effect

Male ddy mice (supplied from the firm Nippon Charles Liver) of 6 weeksage were subcutaneously administered with glucose in a dose of 2 g/kg.The animals were also treated with either one of test compounds via oralor intraperitoneal administration in a dose of 0.1 ml per 10 grams ofbody weight. After one hour, blood sample was taken from abdominalaorta, from which serum was separated and served as the sample.

Blood Sugar decreasing Effect

The samples prepared as above were analyzed for the serum glucoseconcentration by Auto analyzer (SUPER Z of the firm M.C. Medical). Forthe analyzer kit, Glucose II HA TEST WAKO (of the firm Wako PureChemical) was used.

% decrease in blood sugar=[(A-B)/(A-C)]×100 in which A represents theglucose concentration upon being loaded with glucose, B represents theglucose concentration after administration of the compound and C is theusual level of the glucose concentration.

The compound of Example 31 exhibited a blood sugar reduction as high as34.5% by oral administration and the compound of Example 2 showed a77.1% reduction of blood sugar by intraperitoneal administration.Therefore, it was proven that the compound according to the presentinvention is effective as a medicament for therapuetic and preventivetreatment of diabetes.

Lipolytic Effect

Amount of free fatty acid in the samples was determined using NEFA HATEST WAKO (of the firm Wako Pure Chemical). The compounds of Examples 31and 7 have shown that they increased 32.4% and 47.7% by an oraladministration of 30 and 100 mg/kg, respectively. The compound ofExample 2 showed an increase of 67.2% by an intraperitonealadministration of 10 mg/kg. This shows that these compounds havelypolytic activity. Therefore, it was shown that they are useful asmedicament for preventive and therapeutic treatment of hyperlipemia andfor therapeutic treatment of obesity.

Test Example 5

Toxicity Test

The compounds of Examples 7 and 31 were administered to 6 week age maleddy mice (supplied from the firm Nippon Charles Liver) at a dose of 100mg/kg. For all 8 mice, no fatal case was found, which was the case forother compounds, so that the compound according to the present inventionexhibits low toxicity.

Effect of the Invention

The compounds according to the present invention are novel and areuseful for use in drug composition for therapuetic and preventivetreatment of β3-correlating diseases, such as diabetes, obesity andhyperlipemia.

                  TABLE 1                                                         ______________________________________                                        Compound                         MS                                           No.     1H-NMR(CDCl.sub.3): δ(ppm), J(Hz)                                                                m/z                                          ______________________________________                                        Intermed.                                                                             3.47(2H, t, J=6.0), 3.61(2H, q,                                       0       J=6.0), 5.11(1H, s), 5.29(1H,                                                 brs), 7.30˜7.38(5H, m)                                          Intermed.                                                                             (DMSO-d6): 3.44(2H, bt), 4.08                                                                          3.61                                         1       (2H, t, J=5.7), 5.05(2H, s), 6.76(1H,                                                                  (MH+)                                                dd, J=2.1, 8.7), 6.96(1H,                                                     bd, J=2.1), 7.10(1H, dd, J=7.3),                                              7.24˜7.38(6H, m), 7.41(1H,                                              d, J=8.1), 7.52(1H, bt), 7.95(1H,                                             d, J=8.7), 7.97(1H, d, J=7.5),                                                11.08(1H, s)                                                          Intermed.                                                                             (DMSO-d6): 1.8˜2.1(2H, brs),                                                                     227                                          2       2.93(2H, t, J=5.8), 4.00(2H, t,                                                                        (MH+)                                                J=5.8), 6.74(1H, dd, J=2.2, 8.5),                                             6.96(1H, d, J=2.2), 7.10(1H,                                                  dd), 7.27(1H, dd), 7.41(1H                                                    d, J=8.0), 7.95(1H, d, J=8.5),                                                7.97(1H, d, J=7.7), 11.08(1H, s)                                      Example (DMSO-d6): 2.69(d, 2H, J=5.7)2.89(s, 3H),                                                              546                                          1       2.96(t, 2H, J=5.2), 4.09(t, 2H, J=5.2),                                                                (MH+)                                                4.59(m, 1H, 5.15(s, 2H), 5.31(bs, 1H),                                        6.76(dd, 1H, J=8.5, 2.2), 6.96(d, 1H,                                         J=1.9), 7.05˜7.17(m, 3H), 7.25˜7.42(m,                            6H), 7.54(d, 2H, J=6.6), 7.96(t, 2H,                                          J=8.5), 11.08(s, 1H)                                                  Example (DMSO-d6): 2.75(m, 2H), 2.93                                                                           456                                          2       (s, 3H), 3.04(m, 2H), 4.14(t, 2H, J=5.2),                                                              (MH+)                                                4.60(m, 1H), 6.77(dd, 1H, J=8.8, 2.2), 6.85(d,                                1H, J=8.2), 6.97(d, 1H, J=1.9), 7.04(dd, 1H,                                  J=8.2, 1.9), 7.10(m, 1H), 7.21(d, 1H, J=1.9),                                 7.28(dt, 1H, J=8.0, 1.1, 7.41(d, 1H, J=8.0),                                  7.97(m, 2H), 11.10(s, 1H)                                             Intermed.                                                                             3.66(q, 2H, J=5.2), 4.12(t, 2H,                                                                        362                                          4       J=5.2), 5.13(s, 2H), 5.27(bs,                                                                          (MH+)                                                1H), 6.91(dd, 1H, J=8.5, 2.2),                                                7.06(d, 1H, J=2.2), 7.26˜7.41(m,                                        7H), 7.52(dd, 1H, J=8.2, 0.8),                                                7.80(d, 1H, J=8.5), 7.85(m, 1H)                                       Intermed.                                                                             3.14(t, 2H, J=5.2), 4.09(t, 2H,                                                                        228                                          5       J=5.2), 6.96(dd, 1H, J=8.5, 2.2),                                                                      (MH+)                                                7.10(d, 1H, J=2.2), 7.28˜7.41(m,                                        2H), 7.52(m, 1H), 7.81(d, 1H, J=8.5),                                         7.86(m, 1H)                                                           Example DMSO-d6): 2.71(d, 2H, J=5.5),                                                                          547                                          3       2.94(s, 3H), 2.98(m, 2H), 4.14(m,                                                                      (MH+)                                                2H), 4.60(m, 1H, 5.13(bs, 1H), 5.16(s,                                        2H), 5.31(bs, 1H), 7.00(dd, 1H, J=8.5, 2.4),                                  7.07(d, 1H, J=8.5), 7.15(dd, 1H, J=8.5, 2.2),                                 7.26˜7.48(m, 7H), 7.54(m, 2H), 764(dd,                                  1H, J=7.4, 0.8), 8.00(d, 1H, J=8.5),                                          8.04(m, 1H)                                                           Example DMSO-d6): 2.68(d, 2H, J=6.3),                                                                          457                                          4       2.92(s, 3H), 2.96(t, 2H, J=5.5),                                                                       (MH+)                                                4.13(t, 2H, J=5.5), 4.54(m, 1H), 6.83(d,                                      1H, J=8.2), 7.01(septet, 2H), 7.19(d, 1H, J=2.2),                             7.30(d, 1H, J=2.2), 7.35(dt,                                                  1H, J=7.4, 1.1), 7.42(dt, 1H,                                                 J=7.4, 1.4), 7.64(d, 1H, J=8.0),                                              8.00(d, 1H, J=8.8), 8.03(d, 1H, J=7.4)                                Intermed.                                                                             2.68(s, 3H), 7.42(dd, 1H, J=10.2),                                    6       8.4), 8.26(ddd, 1H, J=8.4,                                                    4.2, 2.1), 8.65(dd, 1H, J=7.2, 2.1)                                   Intermed.                                                                             2.55(s, 3H), 3.88(bs, 2H), 7.04(ddd,                                  7       1H, J=10.5, 8.4, 0.6, 7.28˜7.35(m,                                      1H), 7.41(ddd, 1H, J=8.7, 2.1, 0.6)                                   Intermed.                                                                             2.61(s, 3H), 3.09(s, 3H), 6.69                                        8       (bs, 1H), 7.25(dd, 1H, J=9.9, 9.6),                                           7.82(ddd, 1H, J=8.4, 4.8, 2.1),                                               8.17(dd, 1H, J=7.5, 2.1)                                              Intermed.                                                                             3.16(s, 3H), 4.41(s, 2H), 6.62(bs,                                    9       1H), 7.28(t, 1H, J=9.0), 7.86(ddd,                                            1H, J=8.7, 4.8, 2.1), 8.21(dd,                                                1H, J=7.5, 2.1)                                                       Example (DMSO-d6: HCl): 3.05(s, 3H), 3.13(m,                                                                   458                                          5       1H), 3.31(m, 1H), 3.49(m, 2H),                                                                         (MH+)                                                4.38(m, 2H), 4.99(m, 2H), 6.31(d, 1H,                                         J=4.2), 6.84(dd, 1H, J=8.4, 2.4),                                             7.03(d, 1H, J=1.8), 7.12(m, 1H),                                              7.26˜7.38(m, 3H), 7.42˜7.50(m, 2H), 8.01(m,                       2H), 8.97(bs, 2H), 9.71(m, 1H),                                               11.19(s, 1H)                                                          Intermed.                                                                             2.65(s, 3H), 7.68(d, 1H, J=8.4),                                      10      8.09(dd, 1H, J=8.7, 2.1), 8.43(d,                                             1H, J=2.1)                                                            Intrmed.                                                                              2.55(s, 3H), 4.19(bs, 2H), 7.23˜                                11      7.37(m, 3H)                                                           Intermed.                                                                             2.61(s, 3H), 3.07(s, 3H), 6.86                                        12      (bs, 1H), 7.54(d, 1H, J=8.4), 7.75(dd,                                        1H, J=8.4, 2.1), 8.21(d,                                                      1H, J=2.1)                                                            Intermed.                                                                             3.10(s, 3H), 4.41(s, 2H), 6.90(bs,                                    13      1H), 7.58(d, 1H, J=8.4), 7.78(dd,                                             1H, J=8.4, 2.1), 8.24(d, 1H, J=2.1)                                   Example (DMSO-d6; HCl): 3.06(s, 3H), 3.17(m,                                                                   474                                          6       1H), 3.27(m, 1H), 3.48(m, 2H), 4.38(m,                                                                 (NH+)                                                2H), 5.00(m, 1H), 6.35(d, 1H, J=4.2),                                         6.84(dd, 1H, J=8.4, 2.7), 7.02(d, 1H,                                         J=2.1), 7.12(m, 1H), 7.27˜7.34                                          (m, 2H), 7.44(d, 1H, J=7.8), 7.52˜7.59(m,                               2H), 8.01(m, 2H), 8.91(bs, 2H),                                               9.55(m, 1H), 11.17(s, 1H)                                             Example (DMSO-d6): 2.72( m, 2H), 2.96(s,                                                                       440                                          7       3H), 2.98(m, 2H), 4.11(t, 2H,                                                                          (NH+)                                                J=5.7), 4.35(bs, 1H), 4.65(m, 1H),                                            5.40(bs, 1H), 6.76(dd, 1H, J=8.5,                                             2.2), 6.96(d, 1H, J=1.9), 7.07˜7.13(m,                                  3H), 7.24˜7.32(m, 3H, 7.41(d,                                           1H, J=8.2), 7.96(m, 2H), 11.09(s, 1H)                                 Intermed.                                                                             2.58(s, 3H), 4.36(s, 2H), 7.15(bs,                                    15      1H), 7.22˜7.48(m, 6H), 7.62˜7.75(m,                               2H), 8.57(m, 1H)                                                      Example (DMSO-d6): 2.73(m, 2H), 2.98(m,                                                                        516                                          8       2H), 4.11(m, 2H), 4.42(s, 2H),                                                                         (NH+)                                                4.64(m, 1H), 5.38(m, 1H), 6.76(d,                                             1H, J=8.8), 6.96(s, 1H), 7.06˜7.13(m,                                   3H), 7.20˜7.46(m, 9H), 7.96(m, 2H),                                     11.09(s, 1H)                                                          Example 9                                                                             (DMSO-d6): 2.71(m, 2H), 2.96                                                                           441                                          9       (s, 3H), 2.97(m, 2H), 4.14(m, 2H),                                                                     (NH+)                                                4.63(m, 1H), 5.39(bs, 1H), 7.00(dd,                                           1H, J=8.5, 2.2), 7.09(m,                                                      2H), 7.23˜7.46(m, 5H), 7.64(d,                                          1H, J=7.4), 8.02(m, 2H)                                               Intermed.                                                                             2.20(s, 3H), 3.11(t, 2H, J=5.1),                                      17      3.84(s, 2H), 4.04(t, 2H, J=5.2),                                              6.92(m, 1H), 7.08(m, 1H),                                                     7.24˜7.38(m, 3H), 7.58(d, 1H,                                           J=2.2), 7.61(d, 1H, J=2.5), 7.83(s,                                           1H)                                                                   Example (DMSO-d6): 2.05(s, 3H), 2.71                                                                           496                                          10      (m, 2H), 2.94(s, 2H), 2.96(m,                                                                          (NH+)                                                3H), 3.84(s, 2H), 4.07(m, 2H),                                                4.63(m, 1H), 5.39(bs, 1H), 6.92(dd,                                           1H, J=8.5, 2.2), 7.06˜7.15(m,                                           3H), 7.24(s, 1H), 7.27(t, 1H,                                                 J=8.2), 7.46(d, 1H, J=8.2),                                                   7.65(d, 1H, J=2.7), 7.68(d,                                                   1H, J=2.7), 7.86(s, 1H), 9.95                                                 (s, 1H)                                                               Intermed.                                                                             (DMSO-d6): 1.10(d, 3H, J=6.3),                                        18      1.74(bs, 2H), 3.19(m, 1H), 3.80(m,                                            2H), 6.78(dd, 1H, J=8.5, 2.2),                                                6.97(d, 1H, J=1.9), 7.10(t,                                                   1H, J=7.4), 7.28(t, 1H, J=7.4),                                               7.42(d, 1H, J=8.0), 7.92(d, 1H,                                               J=8.5), 7.97(d, 1H, J=8.5),                                                   11.16(s, 1H)                                                          Example (DMSO-d6): 1.10(m, 3H), 2.63(m,                                                                        454                                          11      1H), 2.78(m, 1H), 2.93(s, 3/2H),                                                                       (MH+)                                                2.94(s, 3/2H), 3.06(m, 1H),                                                   3.90(m, 2H), 4.60(m, 1H), 6.75(m,                                             1H), 6.96(dd, 1H, J=8.2, 1.9),                                                7.08(m, 3H), 7.26(m, 3H),                                                     7.42(d, 1H, J=8.0), 7.96                                                      (m, 2H), 11.19(s, 1H)                                                 Intermed.                                                                             2.70(d, 1H, J=3.3), 3.50(dd, 1H,                                      19      J=10.4, 8.5), 3.63(dd, 1H, J=10.4,                                            3.3), 4.92(m, 1H), 5.25(s,                                                    2H), 7.13(d, 1H, J=8.5), 7.30˜                                          7.48(m, 5H), 7.53(dd, 1H, J=8.8,                                              2.5), 7.91(d, 1H, J=2.5)                                              Intermed.                                                                             0.53˜0.62(m, 6H), 0.91(t, 9H,                                   20      J=7.7), 3.31(m, 2H), 4.75(t, 1H,                                              J=5.8), 5.24(s, 2H), 7.13(d,                                                  1H, J=8.8), 7.31˜7.52(m, 6H),                                           7.87(d, 1H, J=2.2)                                                    Intermed.                                                                             0.51˜0.60(m, 6H), 0.89(t, 9H,                                   21      J=7.7), 2.78(dd, 1H, J=11.8, 4.4),                                            2.89(dd, 1H, J=11.8, 7.7),                                                    3.04(m, 2H), 4.12(m, 2H), 4.84(dd,                                            1H, J=7.7, 4.4), 5.19(s,                                                      2H), 6.80˜6.86(m, 2H), 7.05(d,                                          1H, J=8.5), 7.20(m, 1H), 7.30˜                                          7.52(m, 7H), 7.86˜8.09(m, 5H)                                   Intermed.                                                                             0.39˜0.57(m, 6H), 0.77˜0.91(m,                                                             745                                          22      9H), 3.40˜3.52(m, 1H), 3.49                                                                      (M+)                                                 (d, 2H, J=5.2), 3.55˜3.68(m, 1H),                                       3.75(m, 1H), 3.88˜4.17(m,                                               2H), 5.10(s, 2H), 5.14(d, 2H, J=10.2),                                        6.70˜6.83(m, 2H), 7.00(dd,                                              1H, J=18.1, 8.8), 7.20(dd,                                                    1H, J=8.0, 4.7), 7.27˜7.50(m,                                           12H), 7.80˜8.00(m, 4H)                                          Intermed.                                                                             0.40˜0.58(m, 6H), 0.79˜0.92(m,                            23      9H), 3.42˜3.50(m, 3H), 3.49                                             (d, 2H, J=7.7), 3.55˜3.66(m, 1H),                                       3.71(m, 1H), 3.86˜4.16(m,                                               2H), 5.03(d, 2H, J=2.5), 5.18(d,                                              2H, J=16.5), 6.71˜6.85(m, 2H),                                          7.16˜7.45(m, 16H), 7.88(m,                                              1H), 7.96(d, 1H, J=7.1)                                               Intermed.                                                                             0.40˜0.58(m, 6H), 0.79˜0.92(m,                            24      9H), 2.98(s, 3H), 3.42˜3.50(m,                                          1H), 3.49(d, 2H, J=7.7), 3.55˜3.66(m, 1H),                              3.17(m, 1H), 3.86˜4.16(m, 2H), 5.03(d, 2H,                              J=2.5), 5.18(d, 2H, J=16.5),                                                  6.71˜6.85(m, 2H), 7.16˜7.45(m,                                    16H), 7.88(m, 1H), 7.96(d, 1H,                                                J=7.1)                                                                Intermed.                                                                             2.86(d, 1H, J=3.6), 3.56(dd, 1H,                                      25      J=10.7, 8.5), 3.70(dd, 1H,                                                    J=10.7, 3.6), 5.06(dt, 1H, J=8.5                                              3.6), 7.58(t, 1H, J=7.7), 7.75(ddd,                                           1H, J=7.7, 1.1, 0.5), 8.20(m,                                                 1H), 8.30(dd, 1H, J=2.2, 1.6)                                         Intermed.                                                                             (DMSO-d6): 0.50(m, 6H), 0.83(m,                                       28      9H), 2.72(m, 2H), 2.96(s, 3H),                                                2.98(m, 2H), 4.08(m, 2H), 4.75                                                (m, 1H), 5.04(s, 2H), 6.76(dd,                                                1H, J=8.8, 2.2), 6.96(d, 1H,                                                  J=1.9), 7.07˜7.13(m, 3H), 7.24˜                                   7.32(m, 3H), 7.41(d, 1H, J=8.2),                                              7.96(m, 2H), 11.09(s, 1H)                                             Intermed.                                                                             2.72(s, 3/2H), 2.73(s, 3/2H),                                         29      4.46(s, 2H), 7.70(dd, 1H, J=7.8,                                              7.8), 8.11(ddd, 1H, J=7.8, 1.8),                                              8.21(ddd, 1H, J=7.8, 1.8),                                                    8.45(dd, 1H, J=1.8, 1.8)                                              Example (DMSO-d6; HCl): 2.41(d, 3H), 3.16(m,                                                                   440                                          16      1H), 3.35(m, 1H), 3.49(m,                                                                              (MH+)                                                2H), 4.42(m, 2H), 5.21(d, 1H,                                                 J=10.4), 6.48(bs, 1H), 6.84(d,                                                1H, J=8.2), 7.40(d, 1H, J=1.9),                                               7.11(t, 1H, J=7.4), 7.29(m,                                                   1H), 7.44(d, 2H, J=8.0Hz), 7.50˜                                        7.78(m, 4H), 7.88(s, 1H), 8.00                                                (d, 2H, J=8.0), 9.22(bs, 1H),                                                 9.56(bs, 1H), 11.29(s, 1H)                                            Example (DMSO-d6; HCl): 3.16(m, 1H, 3.28(m,                                                                    390                                          17      1H), 3.50(m, 2H), 4.41(m,                                                                              (MH+)                                                2H), 5.08(m, 1H), 6.84(dd, 1H,                                                J=8.2, 2.2), 7.03(d, 1H, J=1.9),                                              7.11(t, 1H, J=7.4), 7.15˜7.55(m,                                        7H), 7.74(m, 1H), 8.01(m,                                                     2H), 9.09(bs, 1H), 9.38(bs,                                                   1H), 11.25(s, 1H)                                                     Example (DMSO-d6): 2.77(m, 2H), 3.00(t,                                                                        408                                          18      2H, J=5.5), 4.12(t, 2H, J=5.5),                                                                        (MH+)                                                4.68(m, 1H), 5.17(br.s, 1H),                                                  6.76(dd, 1H, J=8.5, 2.2), 6.96(d,                                             1H, J=2.2), 7.09(m, 2H),                                                      7.28(m, 1H), 7.41(d, 1H, J=8.0),                                              7.53(dd, 1H, J=8.8, 2.2), 7.87(d,                                             1H, J=2.2), 7.97(m, 2H),                                                      11.10(s, 1H)                                                          Example (DMSO-d6; 2HCl): 3.06(1H, m),                                                                          378                                          19      3.20(1H, m), 3.49(2H, m), 4.39                                                                         (MH+)                                                (2H, m), 4.95(1H, m), 6.19(1H,                                                br.s), 6.84(1H, dd, J=8.5, 2.2),                                              7.00(1H, d, J=8.5), 7.03(1H,                                                  d, J=2.2), 7.12(2H, m), 7.30(2H,                                              m), 8.01(2H, m), 8.96(1H, br.s),                                              9.19(1H, br.s), 10.60(1H,                                                     br.s), 11.21(1H, s)                                                   Example (CD3OD): 3.20˜3.29(2H, m), 3.53(2H,                                                              505                                          20      t, J=4.7), 4.38(2H, t, J=4.7),                                                                         (MH+)                                                4.90(1H, m), 5.07(2H, s),                                                     6.82(1H, d, J=8.2), 6.87(1H,                                                  dd, J=8.5, 2.2), 6.95(1H, dd,                                                 J=8.2, 1.9), 7.05(1H, d, J=1.1),                                              7.12(1H, dd, J=7.1, 1.1), 7.18˜                                         7.46(7H, m), 7.86(1H, d, J=1.9),                                              7.94(2H, d, J=8.5)                                                    Example 21                                                                            (DMSO-d6): 3.00(1H, m), 3.11                                                                           415                                          21      (1H, m), 3.39(2H, m, 4.33(2H,                                                                          (MH+)                                                m), 4.80(1H, m), 5.86(1H, m), 6.25(2H,                                        s), 6.79(2H, s), 6.83(1H,                                                     dd, J=8.5, 2.2), 7.02(1H, d,                                                  J=2.5), 7.12(1H, m)7.30(1H,                                                   m), 7.44(1H, d, J=8.2), 7.90˜8.02(3H,                                   m), 8.08(1H, s), 8.60(1H, br.s),                                              10.02(1H, s), 11.17(1H, s)                                            Example (CD3OD): 2.92(1H, m), 3.04(1H,                                                                         490                                          22      m), 3.63(2H, m), 4.18(2H, m),                                                                          (MH+)                                                4.82(1H, 5.11(2H, s), 6.73                                                    (1H, dd, J=8.5, 2.2), 6.80(1H,                                                d, J=8.2), 6.88(1H, m), 6.93(1H,                                              d, J=1.9), 7.10(1H, dd, J=8.2),                                               7.24˜7.52(8H, m), 7.86˜7.95(2H, m)                        Example (DMSO-d6; HCl): 2.82˜3.00(2H,                                                                    400                                          23      m), 3.44(2H, m), 4.34(2H, m),                                                                          (MH+)                                                4.46(1H, m), 6.83(2H, s), 6.86                                                (1H, m), 7.04(1H, d, J=2.2),                                                  7.12(1H, dd, J=8.0), 7.30(1H, dd,                                             J=6.6, 7.7), 7.44(1H, d, J=8.5),                                              7.72(1H, m), 8.02(2H, d, J=8.2),                                              8.91(1H, br.s), 9.28(1H,                                                      br.s), 9.76(1H, s), 11.18(1H, s)                                      Example (DMSO-d6): 2.61(6H, s), 2.73                                                                           575                                          24      (2H, m), 3.00(2H, m), 4.11(2H,                                                                         (MH+)                                                m), 4.61(1H, m), 5.16(2H, s), 5.38(1H,                                        m), 6.76(1H, m), 6.96(1H, s),                                                 7.02(1H, d, J=8.8), 7.10(2H,                                                  m), 7.24˜7.46(6H, m), 7.56(2H, m),                                      7.97(2H, m), 11.09(1H, m)                                             Example (DMSO-d6; HCl): 2.67(6H, s), 3.04(1H,                                                                  485                                          25      m,), 3.18()1H, m), 3.45(2H, m),                                                                        (MH+)                                                4.39(2H, m), 4.93(1H, m), 6.11(1H,                                            br.s), 6.83(1H, dd, J=8.8,                                                    2.2), 6.91(1H, m), 7.03(2H, m),                                               7.11(1H, m), 7.30(1H, m),                                                     7.35(1H, d, J=2.2), 7.44(1H,                                                  d, J=7.7), 8.00(2H, m), 8.72                                                  (1H, s), 8.99(1H, br.s), 9.28                                                 (1H, br.s), 10.07(1H, s), 11.25                                               (1H, s)                                                               Example (DMSO-d6; 2HCl): 2.81(s, 3H),                                                                          482                                          26      3.17(m, 1H), 3.27(m, 1H), 3.48(m,                                                                      (MH+)                                                2H), 4.38(m, 2H), 5.00(m, 2H),                                                6.35(d, 1H, J=4.2), 6.84(dd,                                                  1H, J=8.4, 2.7), 7.02(d, 1H,                                                  J=2.1), 7.12(m, 1H), 7.27˜7.34(m,                                       2H), 7.44(d, 1H, J=7.8), 7.52˜                                          7.59(m, 2H, 8.01(m, 2H), 8.91(bs.                                             2H), 10.21(bs.2H), 11.17(s, 1H)                                       Example (DMSO-d6; 2HCl): 2.80(s, 3H),                                                                          392                                          27      3.17(m, 1H), 3.27(m, 1H), 3.48                                                                         (MH+)                                                (m, 2H), 4.38(m, 2H), 5.00(m, 2H),                                            6.35(d, 1H, J=4.2), 6.84(dd, 1H,                                              J=8.4, 2.7), 7.02(d, 1H,                                                      J=2.1), 7.12(m, 1H), 7.27˜7.34                                          (m, 2H), 7.44(d, 1H, J=7.8),                                                  7.52˜7.59(m, 2H), 8.01(m, 2H),                                          8.91(bs, 2H), 9.55(m, 1H), 10.21(bs,                                          2H), 11.17(s, 1H)                                                     Intermed.                                                                             2.79(dd, 1H, J=5.7, 2.7), 3.17                                        30      (dd, 1H, J=5.7, 4.2), 4.15(m,                                                 1H), 7.01˜7.31(m, 4H)                                           Example (DMSO-d6; HCl): 3.19(m, 1H), 3.32(m,                                                                   365                                          28      1H), 3.49(m, 2H), 4.40(t,                                                                              (MH+)                                                2H, J=5.1), 5.32(m, 1H), 6.34                                                 (d, 1H, J=3.9), 6.84(dd, 1H, J=8.7,                                           2.4), 7.03(d, 1H, J=2.2),                                                     7.12(m, 1H), 7.19˜7.34(m, 3H),                                          7.36˜7.46(m, 2H), 7.59(dt,                                              2H, J=7.5, 1.8), 8.01(d, 2H, J=8.4)                                   Intermed.                                                                             4.39(s, 2H), 5.15(s, 2H), 7.04                                        31      (m, 2H), 7.32˜7.46(m, 5H), 7.97(m, 2H)                          Intermed.                                                                             (DMSO-d6): 2.72(m, 2H), 2.97(t,                                       32      2H, J=5.4), 4.10(t, 2H, J=5.4),                                               4.61(m, 1H), 5.26(bs, 1H),                                                    6.76(dd, 1H, J=8.7, 2.1), 6.93˜6.98(m,                                  3H), 7.09(m, 1H), 7.24˜7.46(m,                                          9H, 7.95(t, 2H, J=8.4),                                                       11.07(s, 1H)                                                          Example (DMSO-d6): 2.69(m, 2H), 2.96                                                                           363                                          29      (m, 2H), 4.10(m, 2H), 4.58(m, 1H),                                                                     (MH+)                                                5.12(bs, 1H), 6.67˜6.78(m,                                              3H), 6.96(d, 1H, J=1.2),                                                      7.06˜7.18(m, 3H), 7.27(m, 1H), 7.41(d,                                  1H, J=8.1), 7.95(m, 2H), 9.21(bs,                                             1H), 11.06(s, 1H)                                                     Intermed.                                                                             (DMSO-d6): 2.62(dd, 1H, J=12.1,                                       33      8.5), 2.83(m, 1H), 2.94(m, 2H),                                               4.07(m, 2H), 5.10(m, 1H), 5.23(bs,                                            1H), 6.76(dd, 1H, J=8.5, 2.2),                                                6.96(m, 2H), 7.03(d, 1H,                                                      J=8.2), 7.11(m, 1H), 7.20(m,                                                  1H), 7.25˜7.33(m, 2H),                                                  7.34˜7.42(m, 3H), 7.94˜7.97 (m,                                   3H), 7.97(m, 2H), 11.11(s, 1H)                                        Example (DMSO-d6: AcOH): 1.89(s, 3H),                                                                          363                                          30      2.69(m, 1H), 2.85(m, 1H), 2.99(m,                                                                      (MH+)                                                2H), 4.13(t, 2H, J=5.2), 4.91(m,                                              1H), 6.77(m, 3H), 6.96˜7.14(m,                                          3H), 7.24˜7.33(m, 2H),                                                  7.41(d, 1H, J=8.0), 7.97(m, 2H),                                              11.10(s, 1H)                                                          Example (DMSO-d6): 2.6˜2.67(2H, m),                                                                      347                                          31      2.97(2H, bt), 4.11(2H, bt), 4.66                                                                       (MH+)                                                (1H, bt), 5.33(1H, brs), 6.76                                                 (1H, dd, J=2.1, 8.4), 6.96(1H,                                                d, J=2.1), 7.10(1H, dd, J=8.0),                                               7.2˜7.38(6H, m), 7.41(1H, d,                                            J=7.8), 7.95(1H, d, J=8.7), 7.97                                              (1H, d, J=7.5), 11.08(1H, s)                                          Example 2.83(1H, dd, J=9, 12.3), 3.04(1H,                                                                      348                                          34      dd, J=3.6, 12.3), 3.1˜3.16                                                                       (MH+)                                                (2H, m), 4.19(2H, t, J=5.1), 4.78                                             (1H, dd, J=3.6, 9), 7.04(1H, dd,                                              J=2.7, 9.0), 7.26˜7.48(9H,                                              m), 7.55(1H, bd, J=8.4), 7.90                                                 (1H, bd)                                                              Example (DMSO-d6): 1.12(3H, d, J=6.3),                                                                         361                                          35      2.77(2H, d, J=6.0), 3.07(1H,                                                                           (MH+)                                                q, J=6.3), 3.42(2H, t, J=6.0),                                                4.49˜4.56(1H, m), 4.60˜4.66                                       (1H, m), 4.71(1H, t, J=5.8), 5.32(1H, bd),                                    6.73(1H, dd, J=2.2, 6.3),                                                     6.94(1H, d, J=2.2), 7.10(1H,                                                  dd), 7.20˜7.39(6H, m), 7.42                                             (1H, d, J=8.0), 7.95(1H, d,                                                   J=8.8), 7.98(1H, d, J=9.0),                                                   11.08(1H, s)                                                          Intermed.                                                                             (DMSO-d6): 1.85(s, 3H), 3.45(q,                                       34      2H, J=5.8), 4.06(t, 2H, J=5.8),                                               6.77(dd, 1H, J=8.5, 2.2), 6.97                                                (d, 1H, J=2.2), 7.10(m, 1H),                                                  7.28(m, 1H), 7.41(d, 1H, J=8.0),                                              7.97(m, 2H), 8.15(m, 1H), 11.11(s, 1H)                                Intermed.                                                                             1.85(s, 3H), 3.49(1, 2H, J=5.8),                                      35      4.23(t, 2H, J=5.8), 7.22(m,                                                   2H), 7.41(m, 1H), 7.52(d, 1H, J=8.0),                                         8.10(m, 1H), 8.18(d, 1H,                                                      J=8.2), 8.81(s, 1H), 11.74(bs,                                                1H)                                                                   Intermed.                                                                             (DMSO-d6): 2.75(m, 2H), 3.02(t,                                                                        392                                          37      2H, J=5.5), 4.27(t, 2H, J=4.7),                                                                        (MH+)                                                4.66(m, 1H), 5.31(d, 1H, J=4.1),                                              7.18˜7.26(m, 3H), 7.27˜7.45(m,                                    5H, 7.52(d, 1H, J=8.0),                                                       8.19(d, 1H, J=8.0), 8.83(s,                                                   1H), 11.71(s, 1H)                                                     Example (DMSO-d6): 2.73(m, 2H), 3.03(t,                                                                        378                                          36      2H, J=5.6), 4.27(t, 2H, J=4.8),                                                                        (MH+)                                                4.65(m, 1H), 5.31(d, 1H, J=4.1),                                              7.16˜7.25(m, 3H), 7.27˜7.46(m,                                    5H), 7.52(d, 1H, J=8.0), 8.18(d, 1H,                                          J=8.0), 8.83(s, 1H), 11.71(s, 1H)                                     Intermed.                                                                             (CDCl3): 3.66(2H, m), 4.13(2H,                                                                         378                                          38      m), 5.12(2H, s), 5.26(1H, br.s), 7.01(1H,                                                              (MH+)                                                dd, J=8.8, 2.2), 7.23˜7.50(8H,                                          m), 7.80(1H, m), 7.99˜8.60(2H, m)                               Intermed.                                                                             (DMSO-d6): 2.93(2H, t, J=5.8),                                                                         244                                          39      4.04(2H, t, J=8.8, 2.5), 7.39˜                                                                   (MH+)                                                7.49(2H, m), 7.61(1H, d, J=2.5),                                              7.95(1H, dd, J=6.9, 1.9), 8.23(2H, m)                                 Example (CDCl3): 2.82˜2.95(2H, m), 2.91                                                                  563                                          37      (3H, s), 3.09(2H, m), 3.95(3H,                                                                         (MH+)                                                br.s), 4.18(2H, t, J=5.2), 4.75                                               (1H, m), 5.11(2H, s), 6.99(1H, d,                                             J=8.5), 7.05(1H, dd, J=8.5,                                                   2.2), 7.18(1H, dd, J=8.5, 2.2,                                                7.34(1H, d, J=2.5), 7.35˜                                               7.46(7H, m, 7.51(1H, d, J=1.9),                                               7.80(1H, m), 8.03(1H, d, J=8.8),                                              8.05(1H, dd, J=6.3, 1.4)                                              Example (DMSO-d6; HCl): 2.95(3H, s),                                                                           473                                          38      3.08(1H, m), 3.22(1H, m), 3.47                                                                         (MH+)                                                2H, m), 4.44(2H, m), 4.92(1H, m),                                             6.12(1H, d, J=3.8), 6.94(1H,                                                  d, J=8.2), 7.09(1H, dd, J=8.2,                                                1.9), 7.17(1H, dd, J=8.5, 2.2),                                               7.27(1H, d, J=1.9), 7.46(2H                                                   m), 7.69(1H, d, J=2.2), 7.98                                                  (1H, m), 8.27(2H, m), 8.82(1H, br.                                            s), 9.06(2H, br.s), 10.06(1H, s)                                      Intermed.                                                                             (CDCl3): 2.87(6H, s), 4.39(2H,                                                                         427                                          40      s), 5.20(2H, s), 6.89(1H, br.                                                                          (M+)                                                 s), 7.03(1H, dd, J=8.5, 2.7), 7.35˜                                     7.46(5H, m), 7.74(1H, dd,                                                     J=8.5, 2.2), 8.10(1H, d, J=2.2)                                       Example (DMSO-d6): 2.61(6H, m), 2.67(2H,                                                                       592                                          39      d, J=6.6), 2.95(2H, m), 4.13                                                                           (MH+)                                                (2H, m), 4.56(1H, m), 5.16(2H,                                                s), 5.28(1H, d, J=4.1), 7.01(1H,                                              d, J=8.5), 7.09(2H, dd,                                                       J=8.5, 2.2), 7.33(1H, d, J=7.4),                                              7.35˜7.40(3H, m), 7.44(2H, m),                                          7.55(2H, m), 7.60(1H, d, J=2.5),                                              7.96(1H, m), 8.23(2H, m)                                              Example (DMSO-d6; HCl): 2.67(6H, s), 2.99                                                                      502                                          40      (1H, m), 3.12(1H, m), 3.12(1H,                                                                         (MH+)                                                3.35(1H, s), 3.39(2H, m), 4.84(1H,                                            m), 5.98(1H, br.s), 6.88(1H,                                                  d, J=8.2), 7.02(1H, dd,                                                       J=8.2, 1.9), 7.15(1H, dd, J=8.5,                                              2.2), 7.34(1H, d, J=1.9),                                                     7.46(2H, m), 7.67(1H, d, J=2.2),                                              7.98(1H, m), 8.27(2H, m), 8.61(2H,                                            br.s), 10.01(1H, br.s)                                                Example (DMSO-d6; HCl): 3.00(3H, s), 3.08                                                                      457                                          41      (1H, m), 3.26(1H, m), 3.47(2H,                                                                         (MH+)                                                m), 4.43(2H, m), 5.00(1H, m),                                                 6.25(1H, m), 7.12˜7.20(3H,                                              m), 7.30˜7.40(2H, m), 7.40˜7.51                                   (2H, m), 7.69(1H, d, J=2.2),                                                  7.98(1H, m), 8.27(2H, m), 9.05                                                (2H, br), 9.87(1H, br)                                                Intermed.                                                                             (CDCl3): 2.71(1H, br.s), 2.79                                                                          430                                          41      (6H, s), 3.51(1H, dd, J=10.2, 8.5),                                                                    (MH+)                                                3.59(1H, dd, J=10.4, 3.6),                                                    4.48(1H, dd, J=8.5, 3.6), 5.12(2H, s),                                        6.89(1H, br.s), 6.95(1H, d,                                                   J=8.2), 7.09(1H, dd, J=8.5, 1.6),                                             7.33˜7.45(5H, m), 7.52(1H, d, J=1.9)                            Intermed.                                                                             (CDCl3): 0.52˜0.63(6H, m),                                      42      0.87˜0.94(9H, m), 2.77(6H, s),                                          3.28˜3.33(2H, m), 4.71(1H, m),                                          5.10(2H, s), 6.83(1H, br.s),                                                  6.93(1H, dd, J=8.5, 5.2), 7.05                                                (1H, dd, J=8.5, 2.2), 7.37˜7.43                                         (5H, m), 7.50(1H, d, J=2.2)                                           Intermed.                                                                             (CDCl3): 0.50˜0.59(6H, m), 0.89                                                                  690                                          43      (9H, m), 2.76(6H, s), 2.71˜2.79(1H,                                                              (MH+)                                                m), 2.89(1H, dd, J=11.8, 8.2), 3.06(2H,                                       t, J=5.2), 4.15(2H, t, J=5.2),                                                4.80(1H, dd, J=8.2, 4.1), 5.09(2H, s),                                        6.90(1H, d, J=8.2), 6.93(1H, dd, J=                                           8.5, 2.2), 7.05(1H, dd, J=8.5, 2.2),                                          7.07(1H, d, J=2.2), 7.29(1H, dd,                                              J=7.4, 1.1), 7.34(1H, dd,                                                     J=5.2, 1.6), 7.36˜7.45(5H,                                              m), 7.49˜7.54(2H, m), 7.80(1H,                                          d, J=8.5), 7.85(1H, m)                                                Example (CDCl3): 2.78(6H, s), 2.72˜2.78                                                                  576                                          42      (1H, m), 2.99(1H, dd, J=11.8,                                                                          (MH+)                                                3.6), 3.11(2H, m), 4.17(2H, m),                                               4.68(1H, m), 5.11(2H, s),                                                     6.93(1H, d, J=8.5), 6.94(1H, dd,                                              J=8.5, 1.9), 7.08˜7.12(2H, m),                                          7.30(1H, m), 7.34(1H, m), 7.36˜                                         7.42(5H, m), 7.52(2H, m), 7.81                                                (1H, d, J=8.5, 7.86(1H, m)                                            Example (DMSO-d6; HCl): 2.67(6H, s), 3.06                                                                      486                                          43      (1H, m), 3.19(1H, m), 3.48(2H,                                                                         (MH+)                                                m), 4.42(2H, m), 4.88(1H, m),                                                 6.11(1H, d, J=3.3), 6.88(1H,                                                  d, J=8.2), 7.03(1H, dd, J=8.2,                                                1.9), 7.07(1H, dd, J=8.8, 2.2),                                               7.41˜7.50(4H, m), 7.66(1H, d,                                           J=8.2), 8.06(2H, m), 8.71(1H,                                                 s), 8.88(1H, br.s), 9.04(1H,                                                  br.s), 10.01(1H, s)                                                   Intermed.                                                                             (CDCl3): 0.50˜0.59(6H, m), 0.88                                                                  745                                          44      (9H, m), 2.17(3H, s), 2.74(1H,                                                                         (MH+)                                                m), 2.76(6H, s), 2.87(1H, dd,                                                 J=11.8, 8.2), 3.02(2H, t, J=4.9),                                             3.77(2H, s), 4.08(2H, t, J=4.9),                                              4.80(1H, dd, J=8.0, 3.8),                                                     5.08(2H, s), 6.86(1H, dd, J=                                                  8.5, 2.2), 6.90(1H, d, J=8.5),                                                7.01(1H, d, J=1.9), 7.04(1H, dd,                                              J=8.5, 1.9), 7.31(1H, dd, J=8.2,                                              1.6), 7.35˜7.44(5H, m), 7.51˜7.58                                 (3H, m), 7.78(2H, m)                                                  Example (CDCl3): 2.18(3H, s), 2.78(6H,                                                                         631                                          44      s), 2.72˜2.78(1H, m), 2.97(1H,                                                                   (MH+)                                                dd, J=11.8, 3.6), 3.07(2H, m),                                                3.77(2H, s), 4.10(2H, m), 4.68                                                (1H, m), 5.10(2H, s), 6.89(1H,                                                dd, J=8.5, 2.2), 6.91(1H, d,                                                  J=8.5), 7.02(1H, d, J=1.9),                                                   7.04(1H, dd, J=8.5, 1.9), 7.32                                                1H, dd, J=8.2, 1.7), 7.35˜7.41                                          5H, m), 7.51˜7.47(3H, m), 7.79                                          (2H, m)                                                               Example (DMSO-d6; HCl): 2.06(3H, s),                                                                           541                                          45      2.67(6H, s), 2.86˜3.10(2H, m),                                                                   (MH+)                                                3.26(2H, m), 3.86(2H, s), 4.24                                                (2H, m), 4.76(1H, m)5.80(1H, br.s),                                           6.85(1H, d, J=8.2), 6.99                                                      (2H, m), 7.18(1H, d, J=2.1),                                                  7.32(1H, d, J=2.1), 7.48(1H, d,                                               J=8.0), 7.70(2H, m), 7.88(1H, s),                                             10.01(1H, s)                                                          Example (DMSO-d6): 2.7˜2.86(2H, m),                                                                      392                                          46      2.92˜3.11(2H, m), 4.07˜4.13(2H,                                                            (MH+)                                                m), 4.84(1H, br.s), 5.69(1H,                                                  br.s), 6.76(1H, dd, J=8.5, 2.2),                                              6.96(1H, d, J=2.2), 7.10(1H,                                                  dd, J=8.0, 8.0), 7.27(1H, dd,                                                 J=8.0, 8.0), 7.41(1H, d, J=8.0),                                              7.62(1H, d, J=8.0, 8.0), 7.84(1H, d,                                          J=8.0), 7.95(1H, d, J=8.5), 7.98(1H,                                          d, J=8.0), 8.10(1H, m), 8.25(1H, br.s),                                       11.09(1H, s)                                                          Example (DMSO-d6): 2.68(2H, d, J=6.3),                                                                         362                                          47      2.96(2H, br.t, J=5.5), 4.10(2H,                                                                        (MH+)                                                br.t, J=5.5), 4.50(1H, br.t),                                                 4.96(2H, s), 5.14(1H, br.s),                                                  6.42(1H, d, J=7.7), 6.48(1H,                                                  d, J=7.7), 6.59(1H, br.s), 6.76                                               (1H, dd, J=8.5, 2.2), 6.94(1H,                                                dd, J=7.7, 7.7), 6.96(1H, d,                                                  J=2.2), 7.10(1H, dd, J=8.0, J=8.0),                                           7.27(1H, dd, J=8.0, 8.0),                                                     7.41(1H, d, J=8.0), 7.95(1H,                                                  d, J=8.5), 7.97(1H, d, J=8.0),                                                11.08(1H, s)                                                          Example (DMSO-d6): 2.89(6H, s), 2.94˜                                                                    469                                          48      3.02(2H, m), 3.29˜3.36(2H, m),                                                                   (MH+)                                                4.10(2H, br.t), 4.63(1H, br.s),                                               5.41(1H, br.s), 6.76(1H, d,                                                   J=8.8), 6.95(1H, s), 7.0˜7.13                                           (3H, m), 7.2˜7.3(3H, m), 7.92˜8.0                                 (2H, m), 11.09(1H, s)                                                 Example (DMSO-d6): 2.06(3H, s), 2.68(2H,                                                                       602                                          49      d, J=6.0), 2.89(3H, s), 2.93                                                                           (MH+                                                 (2H, m), 3.83(2H, s), 4.06(2H, m),                                            4.58(1H, m), 5.16(2H, s),                                                     5.30(1H, br.s), 6.92(1H, dd, J=8.2,                                           1.9), 7.07(1H, d, J=8.5),                                                     7.15(2H, m), 7.26˜7.50(5H, m),                                          7.53(2H, m), 7.67(2H, m), 7.85(1H,                                            s), 9.95(1H, s)                                                       Example (DMSO-d6; HCl): 2.06(3H, s), 2.95(3H,                                                                  512                                          50      s), 3.05(1H, m), 3.20(1H,                                                                              (MH+)                                                m), 3.42(2H, m), 3.87(2H, s),                                                 4.34(2H, m), 4.89(1H, m), 6.08                                                (1H, s), 6.93(1H, d, J=8.5),                                                  6.99(1H, m), 7.08(1H, d, J=9.6),                                              7.20(1H, s), 7.26(1H, s), 7.48                                                (1H, d, J=8.5), 7.70(2H, m),                                                  7.89(1H, s), 8.86(2H, br.s), 10.03                                            (2H, br)                                                              Example (DMSO-d6): 2.73(1H, dd, J=12.1,                                                                        560                                          51      9.6), 2.90(3H, s), 2.99(1H,                                                                            (MH+)                                                dd, J=12.1, 3.6), 3.07(2H, q, J=                                              4.9), 3.49(1H, s), 3.77(2H, s),                                               4.11(2H, t, J=4.9), 4.67(1H,                                                  dd, J=9.6, 3.6), 5.10(2H, s),                                                 6.69(1H, dd, J=8.2, 2.2), 6.86                                                (2H, m), 6.97(1H, d, J=8.5), 7.04                                             (1H, m), 7.18(1H, dd, J=8.8,                                                  1.9), 7.32˜7.50(7H, m), 7.53                                            (1H, m)                                                               Example (DMSO-d6; 2HCl): 2.95(3H, s),                                                                          470                                          52      3.07(1H, m), 3.17(1H, m), 3.43                                                                         (MH+)                                                (2H, m), 3.94(2H, s), 4.37(2H,                                                m), 4.91(1H, m), 6.09(1H, br.s),                                              6.94(1H, d, J=8.5), 7.05(2H, m),                                              7.25(3H, m), 7.45(1H, s),                                                     7.83(2H, m), 8.82(1H, s), 8.94                                                (1H, br.s), 9.22(1H, br.s) 9.80(1H,                                           br), 10.06(1H, s), 10.03(2H, br.s)                                    Intermed.                                                                             (CDCl3): 1.36(6H, d, J=9.6), 3.29                                     45      (1H, m), 4.40(2H, s), 5.20(2H,                                                s), 6.79(1H, s), 7.05(1H, d,                                                  J=8.5), 7.35˜7.47(5H, m), 7.78                                          (1H, dd, J=8.5, 2.2), 8.21(1H,                                                d, J=3 2.2)                                                           Example (DMSO-d6): 1.16(6H, d, J=6.9),                                                                         574                                          53      2.69(2H, d, J=6.3), 2.96(2H,                                                                           (MH+)                                                t, J=5.2), 3.12(1H, m), 4.10(2H,                                              t, J=5.2), 4.58(1H, m), 5.14                                                  (2H, s), 5.31(1H, m), 6.76(1H,                                                dd, J=8.8, 1.7), 6.96(1H, d, J=                                               1.9), 7.02˜7.15(3H, m), 7.25˜                                     7.44(6H, m), 7.54(2H, m), 7.97                                                (2H, m), 11.10(1H, s)                                                 Example (DMSO-d6; HCl): 1.27(6H, d, J=                                                                         484                                          54      6.9), 2.95˜3.28(3H, m), 3.47(2H,                                                                 (MH+)                                                m), 4.39(2H, m), 4.91(1H, m),                                                 6.11(1H, br.s), 6.84(1H, dd,                                                  J=8.5, 2.2), 6.92(1H, m), 7.05                                                (2H, m), 7.12(1H, t, J=7.4), 7.30                                             (2H, m), 7.44(1H, d, J=8.2),                                                  8.00(2H, m), 8.73(1H, s), 8.94                                                (1H, m), 9.18(1H, br.s), 10.07                                                (1H, s), 11.23(1H, s)                                                 Intermed.                                                                             (CDCl3): 0.52˜0.62(6H, m),                                      46      0.87˜0.94(9H, m), 3.03(3H, s), 3.3˜                               3.34(2H, m), 4.74(1H, m), 6.54(1H,                                            br.s), 7.08˜7.2(2H, m), 7.57(1H,                                        dd, J=7.6, 2.2)                                                       Intermed.                                                                             (CDCl3): 0.51˜0.6(6H, m),                                       47      0.85˜0.92(9H, m), 2.78(1H, dd, J=11.8,                                  4.0), 2.87(1H, dd, J=11.8,                                                    8.0), 3.00(3H, s), 3.06(2H, t,                                                J=5.2), 4.16(2H, t, J=5.2),                                                   4.84(1H, dd, J=8.0, 4.0), 6.93                                                (1H, dd, J=8.5, 2.2), 7.08(1H,                                                d, J=2.2), 7.10(1H, m),                                                       7.15˜7.21(1H, m), 7.31(1H, m,                                           7.38(1H, m), 7.52(1H, d, J=8.2), 7.59                                         (1H, dd, J=8.0, 2.2), 7.81(1H, d,                                             J=8.5), 7.86(1H, m)                                                   Example (DMSO-d6; HCl): 3.05(3H, s), 3.12                                                                      459                                          55      (1H, m), 3.29(1H, m), 3.48(2H,                                                                         (MH+)                                                m), 4.43(2H, m), 5.01(1H, m),                                                 6.31(1H, d, J=4.4), 7.08(1H,                                                  dd, J=8.5, 2.2), 7.29(1H, m),                                                 7.32˜7.50(6H, m), 7.66(1H, d,                                           J=8.0), 8.07(2H, m), 8.96(2H,                                                 m), 9.71(1H, s)                                                       Intermed.                                                                             (CDCl3): 0.55˜0.61(6H, m),                                      48      0.85˜0.92(9H, m), 2.77(1H, dd, J=11.8,                                  4.1), 2.88(1H, dd, J=11.8,                                                    7.8), 2.99(3H, s), 3.06(2H, t,                                                J=5.2), 4.16(2H, t, J=5.2),                                                   4.83(1H, dd, J=7.8, 4.1), 7.04(1H,                                            dd, J=8.8, 2.5), 7.10(1H, m),                                                 7.15˜7.21(1H, m), 7.32(1H,                                              d, J=2.2), 7.35˜7.46(2H, m),                                            7.58(1H, dd, J=7.7, 2.1), 7.80(1H,                                            m), 8.03(1H, d, J=8.8), 8.04(1H, m)                                   Example (DMSO-d6; HCl): 3.05(3H, s), 3.11(1H,                                                                  475                                          56      m), 3.32(1H, m), 3.49(2H, m),                                                                          (MH+)                                                4.42(2H, m), 4.98(1H, m), 6.31(1H,                                            d, J=3.3), 7.17(1H, dd, J=8.8, 2.5),                                          7.27˜7.37(2H, m), 7.43˜7.52(3H, m),                               7.69(1H, d, J=2.5), 7.98(1H, m),                                              8.28(2H, m), 8.95(2H, br.s), 9.71(1H, s)                              Intermed.                                                                             (CDCl3): 0.54˜0.63(6H, m),                                      49      0.87˜0.95(9H, m), 3.02(3H, s),                                          3.28˜3.34(2H, m), 4.74(1H, m),                                          6.81(1H, br.s), 7.16(1H, dd, J=8.2,                                           2.2), 7.40(1H, d, J=8.2), 7.65(1H, d, J=2.2)                          Intermed.                                                                             (CDCl3): 0.52˜0.62(6H, m), 0.86˜                          50      0.93(9H, m), 2.80(1H, dd, J=12.0,                                             4.2), 2.88(1H, dd, J=12.0, 8.0),                                              2.98(3H, s), 3.08(2H, t, J=5.2),                                              4.15(2H, t, J=5.2), 4.85(1H,                                                  dd, J=8.0, 4.2), 6.92(1H,                                                     dd, J=8.5, 2.2), 7.08(1H, d,                                                  J=2.2), 7.17(1H, dd, J=8.2,                                                   1.9), 7.28˜7.41(3H, m), 7.5˜7.56(1H, m),                          7.67(1H, d, J=2.2), 7.81(1H, d, J=8.2),                                       7.86(1H, m)                                                           Example (DMSO-d6; HCl): 3.06(3H, s), 3.12                                                                      475                                          57      (1H, m), 3.29(1H, m), 3.48(2H,                                                                         (MH+)                                                m), 4.42(2H, m), 5.01(1H, m), 6.34(1H, m),                                    7.07(1H, dd, J=8.8, 2.2), 7.31(1H, dd,                                        J=8.2, 2.2), 7.34˜7.41(2H, m), 7.45                                     (1H, m), 7.52(1H, d, J=1.9), 7.57(1H,                                         d, J=8.2), 7.66(1H, m), 8.06(2H, m),                                          9.02(2H, br.s)                                                        Intermed.                                                                             (CDCl3): 0.52˜0.62(6H, m),                                      51      0.86˜0.92(9H, m), 2.79(1H, dd, J=12.1,                                  4.1), 2.87(1H, dd, J=12.1,                                                    7.7), 2.97(3H, s), 3.05(2H, br.t),                                            4.15(2H, br.t), 4.84(1H, dd,                                                  J=7.7, 4.1), 7.03(1H, dd, J=8.7,                                              2.5), 7.16(1H, dd, J=8.7, 2.2), 7.31(1H, d,                                   J=3 2.5), 7.35˜7.46(3H, m), 7.66(1H, d,                                 J=2.2), 7.80(1H, m), 8.02(1H, d,                                              J=8.4), 8.04(1H, m)                                                   Example (DMSO-d6; HCl): 3.06(H, s),                                                                            491                                          58      3.08˜3.15(1H, m), 3.27˜3.35(1H,                                                            (MH+)                                                m), 3.44˜3.53(2H, m), 4.40˜4.48(2H,                               m), 5.0˜5.09(1H, m), 6.37(1H, br.s),                                    7.17(1H, dd, J=8.6, 2.2), 7.31(1H,                                            dd, J=8.2, J=1.9), 7.46˜7.57(2H, m),                                    7.53(1H, d, J=1.9), 7.56(1H, d, J=8.2),                                       7.68(1H, d, J=2.5), 7.95˜7.99(1H, m),                                   8.3˜8.3(2H, m), 9.02(1H, br.s), 9.18(1H,                                br.s), 9.55(1H, s)                                                    Intermed.                                                                             (CDCl3): 2.60(3H, s), 2.90(6H,                                        52      s), 6.53(1H, br.s), 7.19(1H, dd,                                              J=8.5, 7.7), 7.73(1H, m), 8.14(1H,                                            dd, 7.7, 2.2)                                                         Intermed.                                                                             (CDCl3): 2.90(6H, s), 4.41(2H,                                        53      s), 6.69(1H, br.s), 7.23(1H,                                                  dd, J=9.9, 8.8), 7.77(1H, ddd,                                                J=7.0, 4.9, 2.2), 8.17(1H, dd,                                                7.4, 2.2)                                                             Example (DMSO-d6; HCl): 2.71(6H, s),                                                                           487                                          59      3.0˜3.14(1H, br.s), 3.22˜3.34                                                              (MH+)                                                (1H, br.s), 3.43˜3.53(2H, m),                                           4.33˜4.46(2H, m), 5.02(1H, m),                                          6.34(1H, br.s), 6.83(1H, dd,                                                  J=8.5, 2.2), 7.03(1H, d, J=2.2),                                              7.12(1H, dd, J=7.7, 7.7), 7.2˜7.38(3H,                                  m), 7.44(1H, d, J=8.0), 7.52(1H,                                              dd, J=7.7, 2.0), 8.00(2H,                                                     d, J=8.5), 8.94˜9.10                                                    (1H, br.s), 9.14˜9.30(1H, br.s),                                        9.71(1H, s), 11.22(1H, s)                                             Intermed.                                                                             (CDCl3): 2.60(3H, s), 2.89(6H,                                        54      s), 6.85(1H, br.s), 7.48(1H, d,                                               J=8.2), 7.65(1H, dd, J=8.2,                                                   1.9), 8.17(1H, d, 1.9)                                                Intermed.                                                                             (CDCl3): 2.90(6H, s), 4.41(2H,                                        55      s), 6.90(1H, br.s), 7.52(1H,                                                  d, J=8.5), 7.68(1H, dd, J=8.5,                                                1.9), 8.20(1H, d, J=1.9)                                              Intermed.                                                                             (CDCl3): 2.79(3H, s), 9.08(2H,                                        56      d, J=2.2), 9.25(1H, dd, J=2.2)                                        Intermed.                                                                             (CDCl3): 2.63(3H, s), 4.19(2H,                                        57      br.s), 7.53(1H, dd, J=2.2), 7.67                                              (1H, dd, J=2.2), 8.10(1H, dd, J=2.2)                                  Intermed.                                                                             (CDCl3): 2.68(3H, s), 6.34(1H,                                        58      br.s), 7.79(1H, dd, J=2.5), 7.92                                              (1H, dd, J=2.2), 8.34(1H, dd, J=1.9)                                  Intermed.                                                                             (CDCl3): 2.66(3H, s), 5.20(2H,                                        59      s), 7.30˜7.48(5H, m), 7.88(1H,                                          dd, J=2.5), 8.01(1H, dd, J=2.5,                                               1.9), 8.36(1H, dd, J=1.9)                                             Intermed.                                                                             (CDCl3): 2.53(3H, s), 3.80(2H,                                        60      br.s), 5.07(2H, s), 6.50(1H,                                                  dd, J=1.9), 6.89(1H, dd, J=1.9),                                              6.98(1H, dd, J=2.2), 7.30˜7.48(5H, m)                           Example (DMSO-d6; HCl): 2.73(6H, s),                                                                           503                                          60      3.0˜3.15(1H, m), 3.24˜3.36(1H,                                                             (MH+)                                                3.4˜3.54(2H, m), 4.35˜4.26(2H,                                    m), 5.05(1H, m), 6.38(1H, br.s), 6.84(1H,                                     dd, J=8.5, 2.2, 7.03(1H, d, J=2.2),                                           7.12(1H, dd, J=8.0, 8.0), 7.23˜7.34                                     (2H, m), 7.44(1H, d, J=8.0), 7.52(1H,                                         d, J=8.2), 7.61(1H, d, J=1.9),                                                8.01(2H, d, J=8.5), 8.94˜9.08(1H,                                       br.s), 9.15˜9.28(1H, br.s), 9.46(1H, s),                                11.22(1H, s)                                                          Intermed.                                                                             (CDCl3): 2.58(3H, s), 3.00(3H,                                        61      s), 5.12(2H, s), 6.88(1H, bs),                                                7.15(1H, d, J=2.2), 7.27˜7.47(7H, m)                            Intermed.                                                                             (CDCl3): 3.02(3H, s), 4.40(2H,                                        62      s), 5.13(2H, s), 6.95(1H, br.s),                                              7.15˜7.18(1H, m), 7.31˜7.50(7H, m)                        Example (CDCl3): 2.74(2H, m), 2.86(3H,                                                                         546                                          61      s), 2.96(2H, m), 4.00(2H, m),                                                                          (MH+)                                                4.68(1H, d, J=5.5), 4.94(2H, s),                                              6.74(4H, m), 6.84(1H, s), 7.18                                                (1H, m, 7.27˜7.39(7H, m), 7.85(1H,                                      d, J=8.5), 7.92(1H, d, J=7.4),                                                8.26(1H, br.s)                                                        Example (DMSO-d6): 2.98(3H, s), 3.23(2H,                                                                       456                                          62      m), 3.47(2H, m), 4.39(2H, t,                                                                           (MH+)                                                J=4.7), 4.91(1H, d, J=10.4),                                                  6.19(1H, d, J=3.6), 6.57(1H, s),                                              6.64(1H, dd, J=1.9), 6.73(1H,                                                 s), 6.84(1H, dd, J=8.8, 2.5),                                                 7.03(1H, d, J=2.2), 7.12(1H,                                                  dd, J=7.4), 7.30(1H, dd, J=7.1),                                              7.44(1H, d, J=8.0)                                                    Intermed.                                                                             (CDCl3): 2.73(3H, s), 7.05(1H,                                        63      dd, J=8.0), 8.06(1H, d, J=8.0),                                               8.20(1H, d, J=8.2)                                                    Intermed.                                                                             (CDCl3): 2.75(3H, s), 7.10(1H,                                                d, J=9.3), 8.36(1H, dd, J=9.3,                                                2.8), 8.72(1H, d, J=2.8)                                              Intermed.                                                                             (CDCl3): 2.66(3H, s), 3.95(3H,                                        65      s), 7.30(1H, d, J=8.0), 7.82(1H,                                              dd, J=8.0, 1.9), 7.93(1H, dd,                                                 J=8.0, 1.9)                                                           Intermed.                                                                             (CDCl3): 2.62(3H, s), 3.78(3H,                                        66      s), 3.92(2H, br.s), 6.89(1H, dd,                                              J=7.1, 2.5), 6.97(1H, d, J=6.9),                                              6.98(1H, d, J=2.5)                                                    Intermed.                                                                             (CDCl3): 2.63(3H, s), 3.08(3H,                                        67      s), 3.82(3H, s), 7.05(1H, br.s),                                              7.19(1H, dd, J=8.0), 7.38 (1H,                                                dd, J=8.0, 1.7), 7.71(1H, dd,                                                 J=8.2, 1.7)                                                           Intermed.                                                                             (CDCl3): 2.61(3H, s), 3.01(3H,                                        68      s), 3.83(3H, s), 4.82(2H, s),                                                 7.06(1H, dd, J=8.0, 7.8), 7.19˜7.30                                     (6H, m), 7.52(1H, dd, J=8.0, 1.9)                                     Intermed.                                                                             (CDCl3): 3.01(3H, s), 3.87(3H, s),                                    69      4.49(2H, s), 4.83(2H, s), 7.11(1H,                                            dd, J=8.0, 7.8), 7.19˜7.31(6H,                                          m), 7.57(1H, dd, J=8.0, 1.9)                                          Intermed.                                                                             (CDCl3): 2.74(1H, d, J=8.8),                                          70      2.93(3H, s), 2.98˜3.14(3H, m),                                          3.80(3H, s), 4.15(2H, m), 4.81                                                (2H, m), 5.04(1H, d, J=8.8), 6.84                                             (1H, d, J=8.5), 6.87(1H, br.s),                                               7.01(1H, d, J=8.0), 7.06(1H, dd,                                              J=7.4), 7.17˜7.40(8H, m), 7.50(1H,                                      d, J=7.4), 7.91(1H, d, J=8.2),                                                7.96(1H, d, J=7.7), 8.12(1H, br.s)                                    Intermed.                                                                             (DMSO-d6): 2.9˜3.1(2H, m), 3.12                                 71      (3H, s), 3.15˜3.30(2H, m),                                              4.34˜4.44(2H, m), 4.76(2H, m),                                          5.30(1H, d, J=9.6), 6.2˜6.4(1H,                                         br.s), 6.78˜6.98(2H, m),                                                7.02˜7.38(10H, m), 7.44(2H, d, J=8.0),                                  7.95(1H, dd, J=7.7, 8.2),                                                     8.01(2H, d, J=8.2)                                                    Example (CD3OD): 2.85(3H, s), 2.96˜3.20                                                                  456                                          63      (4H, m), 4.21(2H, t, J=5.0), 4.98(1H,                                                                  (MH+)                                                m), 6.77(1H, dd, J=7.7), 6.81(1H,                                             dd, J=J=8.9, 2.2), 6.99(1H,                                                   d, J=2.2), 7.07˜7.14(2H, m),                                            7.23˜7.30(2H, m), 7.38(1H,                                              d, J=8.2), 7.91(2H, dd, J=8.2)                                        Intermed.                                                                             (CDCl3): 2.65(3H, s), 4.05(3H,                                        72      s), 7.08(1H, d, J=9.1), 8.36(1H,                                              dd, J=9.1, 3.0), 8.63(1H, d, J=2.8)                                   Intermed.                                                                             (CDCl3): 2.60(3H, s), 3.50(2H,                                        73      br.s), 3.84(3H, s), 6.82(2H, m),                                              7.08(1H, m)                                                           Intermed.                                                                             (CDCl3): 2.63(3H, s), 2.97(3H,                                        74      s), 3.93(3H, s), 6.39(1H, br.s),                                              7.01(1H, d, J=9.1), 7.51˜7.57(2H, m)                            Intermed.                                                                             (CDCl3): 2.59(3H, s), 2.95(3H,                                        75      s), 3.88(3H, s), 4.81(2H, s),                                                 6.87(1H, d, J=9.1), 7.22˜7.28                                           (5H, m), 7.30(1H, dd, J=8.8, 2.8),                                            7.71(1H, d, J=3.0)                                                    Intermed.                                                                             (CDCl3): 2.96(3H, s), 3.92(3H,                                        76      s), 4.56(2H, s), 4.81(2H, s),                                                 6.90(1H, d, J=8.8), 7.22˜7.28                                           (5H, m), 7.37(1H, dd, J=9.1m, 3.0),                                           7.77(1H, d, J=2.8)                                                    Intermed.                                                                             (CDCl3): 2.6˜3.0(2H, m), 2.94                                   77      (3H, s), 3.04˜3.08(2H, m), 3.70(3H,                                     s), 4.14(2H, t, J=5.8), 4.79(2H, d,                                           J=9.9), 4.99(1H, m), 6.60(1H, d),                                             6.80˜6.86(2H, m), 7.03(1H, dd,                                          J=8.5, 3.0), 7.18˜7.42(8H, m),                                          7.88˜8.00(3H, m), 8.07(1H, m)                                   Intermed.                                                                             (CD3OD): 3.01(3H, s), 3.31(2H,                                        78      m), 3.54(2H, m), 4.38(2H, t, J=5.0),                                          4.78˜4.82(2H, m), 5.27(1H, m),                                          6.72˜6.95(2H, m), 7.05(1H, d,                                           J=1.9), 7.08˜7.48(11H,                                                  m), 7.95(2H, d, J=7.1                                                 Example (CD3OD): 2.88(3H, s), 3.19(2H,                                                                         456                                          64      m), 3.62(2H, m), 4.22(2H, m),                                                                          (MH+)                                                5.24(1H, m), 6.72˜7.48(9H, m),                                          7.85˜7.95(2H, m)                                                Intermed.                                                                             (CDCl3): 2.61(3H, s), 5.45(2H,                                        79      s), 7.22(1H, d, J=8.8), 7.34˜                                           7.55(5H, m), 8.267(1H, dd, J=8.8,                                             2.2), 8.55(1H, d, J=2.5)                                              Intermed.                                                                             (CDCl3): 2.57(3H, d, J=5.2),                                          79      2.61(3H, s), 4.70(1H, q, J=5.5),                                              5.32(2H, s), 7.17(1H, d, J=8.8),                                              7.24˜7.51(5H, m), 8.18(1H,                                              dd, J=8.8, 2.2), 8.50(1H, d, J=2.2)                                   Intermed.                                                                             (CDCl3): 2.58(3H, s), 4.43(2H,                                        80      s), 4.74(1H, s), 5.34(2H, s),                                                 7.20(1H, d, J=8.8), 7.36˜7.51                                           (5H, m), 8.20(1H, dd, J=8.8, 2.2),                                            8.52(1H, d, J=2.2)                                                    Example (DMSO-d6): 2.42(3H, d, J=5.0),                                                                         546                                          65      2.71(2H, d, J=6.0), 2.95(2H,                                                                           (MH+)                                                t, J=5.2), 4.08(2H, t, J=5.5),                                                4.64(1H, m), 5.33(2H, s), 5.42                                                (1H, d, J=4.1), 6.75(1H, dd, J=8.5,                                           2.2), 6.93˜7.00(2H, m), 7.10(1H, dd,                                    J=7.7, 7.4), 7.15(1H, d, J=8.5),                                              7.24˜7.54(8H, m), 7.76(1H, d, J=2.2),                                   7.92˜8.00(2H, m), 11.08(1H, s)                                  Example (DMSO-d6; HCl): 2.41(3H, d, J=5.0),                                                                    456                                          66      3.03˜3.35(2H, m), 3.47(2H, m),                                                                   (MH+)                                                4.39(2H, m), 5.00(1H, d, J=10.4),                                             6.21(1H, br.s), 6.84(1H, dd, J=8.5),                                          2.2), 6.88(1H, d, J=5.2), 7.03(1H, d,                                         J=2.2), 7.08(1H, d, J=8.2), 7.13(1H,                                          d, J=8.0), 7.30(1H, ddd, J=8.2,                                               1.1), 7.44(1H, d, J=8.0), 7.47                                                (1H, dd, J=8.8, 2.2), 7.71(1H,                                                d, J=2.2), 8.01(2H, d, J=8.5),                                                8.90˜9.05(1H, br.s), 9.10˜9.25                                    (1H, br.s), 10.89(1H, s), 1.21(1H, s)                                 Intermed.                                                                             (CDCl3): 2.58(3H, s), 3.94(3H,                                        82      s), 5.28(2H, s), 7.07(1H, d, J=8.8),                                          7.30˜7.52(5H, m), 8.08                                                  (1H, dd, J=8.8, 2.5), 8.44(1H,                                                d, J=2.2)                                                             Intermed.                                                                             (CDCl3): 3.94(3H, s), 4.42(2H,                                        83      s), 5.29(2H, s), 7.10(1H, d, J=8.8),                                          7.34˜7.50(5H, m), 8.11(1H,                                              dd, J=8.8, 2.5), 8.47(1H, d,                                                  J=2.2)                                                                Intermed.                                                                             (CDCl3): 2.77(1H, d, J=12.3),                                                                          511                                          84      2.99(1H, d, J=12.3), 3.08(2H,                                                                          (MH+)                                                m), 3.89(3H, s), 4.13(2H, t, J=5.1),                                          4.72(1H, d, J=8.7), 5.14(2H, s), 6.83(2H,                                     m), 6.95(1H, d, J=8.5), 7.20(1H, m),                                          7.30˜7.48(8H, m), 7.84(1H, d, J=2.2),                                   7.91(1H, d, J=9.3), 7.96(1H, d, J=7.7),                                       8.12(1H, br.s)                                                        Intermed.                                                                             (CDCl3): 2.81(1H, d, J=11.8),                                                                          411                                          85      2.99(1H, d, J=12.1, 3.10(2H,                                                                           (MH+)                                                m), 4.17(2H, t, J=5.0), 4.71(1H,                                              m), 4.75(2H, s), 5.12(2H, s),                                                 6.85(1H, d, J=8.5), 6.88(1H,                                                  s), 6.94(1H, d, J'8.2), 7.20˜7.42                                       (9H, m), 7.93(1H, d, J=8.8),                                                  7.97(1H, d, J=7.7), 8.20(1H, br.s)                                    Example (DMSO-d6; HCl): 3.71(1H, br.s),                                                                        393                                          67      3.19(1H, br.s), 3.48(2H, br.s),                                                                        (MH+)                                                4.38(2H, m), 4.49(2H, s), 4.90(1H,                                            d, J=10.2), 5.04(1H, br.s),                                                   6.03(1H, d, J=3.3), 6.78(1H, d,                                               J=8.20, 6.84(1H, dd, J=8.2, 2.2),                                             7.02(1H, d, J=2.2), 7.07(1H,                                                  d, J=7.4), 7.12(1H, dd, J=7.4,                                                7.4), 7.30(1H, dd, J=8.0, 8.0),                                               7.36(1H, s), 7.44(1H, d, J=7.7),                                              8.01(2H, d, J=8.5)                                                    Intermed.                                                                             (CDCl3): 2.73(1H, br.s), 3.03                                         86      (3H, s), 3.53(1H, dd, J=10.44,                                                8.8), 3.66(1H, dd, J=10.44, 3.3),                                             4.94(1H, dd, J=8.8, 3.6), 6.57(1H,                                            br.s), 7.17˜7.24(2H, m),                                                7.26(1H, m), 7.38(1H, m)                                              Intermed.                                                                             (CDCl3): 0.47˜0.68(6H, m), 0.91                                 87      (9H, t, J=7.7), 3.01(3H, s), 3.33                                             (2H, d, J=5.8), 4.75(1H, t, J=5.8),                                           6.49(1H, br.s), 7.13˜7.19(2H, m),                                       7.22(1H, m), 7.33(1H, t, J=7.7)                                       Intermed.                                                                             (CDCl3): 1.58˜1.73(2H, m), 2.00                                 88      (3H, s), 2.20˜2.32(2H, m), 2.35˜                                  2.55(4H, m), 4.25(1H, m),                                                     5.48(1H, br, s)                                                       Intermed.                                                                             (DMSO-d6): 1.75(1H, m), 1.82                                          89      (3H, s), 1.94(1H, m), 2.42(1H,                                                dd, J=14.6, 8.5), 3.73(3H, s),                                                4.01(1H, m), 6.57(1H, dd, J=8.2,                                              2.2), 6.75(1H, d, J=2.2), 7.18                                                (1H, d, J=8.5), 7.93(1H, d, J=8.0),                                           10.50(1H, s)                                                          Intermed.                                                                             (DMSO-d6): 2.05(3H, s), 3.83                                          90      (3H, s), 6.74(1H, dd, J=8.5,                                                  2.2), 6.93(1H, d, J=2.2), 7.30˜7.40                                     (2H, m), 7.86(1H, d, J=8.8),                                                  8.21(1H, d, J=1.9), 9.85(1H, s),                                              11.00(1H, s)                                                          Intermed.                                                                             (DMSO-d6): 2.05(3H, s), 6.60                                          91      (1H, dd, J=8.5, 1.9), 6.77(1H, d,                                             J=1.6), 7.26(1H, d, J=8.5),                                                   7.34(1H, dd, J=8.5, 1.6), 7.74                                                (1H, d, J=3 8.5), 8.15(1H, s), 9.38                                           (1H, s), 9.82(1H, s), 10.83(1H, s)                                    Intermed.                                                                             (DMSO-d6): 2.06(3H, s), 3.43                                          92      (2H, m), 4.07(2H, m), 5.05(2H,                                                s), 6.74(1H, dd, J=8.5, 1.9), 6.94                                            (1H, s), 7.25˜7.50(7H, m),                                              7.54(1H, t, J=5.5), 7.86(1H, m),                                              J=8.5), 8.22(1H, s), 9.86(1H, s),                                             11.02(1H, s)                                                          Intermed.                                                                             (DMSO-d6): 1.8˜2.1(2H, br.s),                                   93      2.05(3H, s), 2.93(2H, t, J=5.8), 4.00(2H,                                     t, J=5.8), 6.74(1H, dd, J=8.5, 2.2), 6.93(1H,                                 d, J=2.2), 7.30˜7.40(2H, m), 7.86(1H, d, J=8.8),                        8.21(1H, d, J=1.9), 9.85(1H, s), 11.00(1H, s)                         Example (DMSO-d6; HCl): 2.06(3H, s), 3.00                                                                      497                                          68      (3H, s), 3.17(1H, m), 3.27(1H,                                                                         (M+)                                                 m), 3.48(2H, m), 4.37(2H, m),                                                 4.97(1H, m), 6.26(1H, m), 6.82(1H, m),                                        6.99(1H, m), 7.15(2H, m), 7.30˜7.40(4H,                                 m), 7.92(1H, d, J=8.8), 8.27(1H, s),                                          8.91(2H, m), 9.86(1H, s), 9.89(1H, s),                                        11.09(1H, s)                                                          Intermed.                                                                             (CDCl3): 0.49˜0.58(6H, m), 0.88                                                                  689                                          95      (9H, m), 2.75(6H, s), 2.72˜2.79                                                                  (MH+)                                                (1H, m), 2.81˜2.94(1H, m),3.01(2H,                                      m), 4.12(2H, m), 4.80(1H, dd, J=7.7,                                          4.1), 5.07(2H, s), 6.82(1H, dd, J=8.5, 2.2),                                  6.93(1H, dd, J=8.5, 2.2), 7.05(1H, dd,                                        J=8.5, 2.2), 7.07(1H, d, J=2.2), 7.29(1H,                                     dd, J=7.4, 1.1), 7.34(1H, dd, J=5.2, 1.6),                                    7.36˜7.45(5H, m), 7.49˜7.54(2H, m), 7.80(1H,                      d, J=8.5), 7.85(1H, m)                                                Intermed.                                                                             (CDCl3): 0.51˜0.60(6H, m), 0.88                                 102     (9H, m), 2.78(1H, dd, J=11.8, 4.1),                                           2.89(1H, dd, J=11.8, 7.7),                                                    2.99(3H, s), 3.05(2H, t, J=4.9),                                              4.15(2H, t, J=4.9), 4.83(1H,                                                  dd, J=7.7, 4.1), 6.82(1H, dd,                                                 J=8.5, 2.2), 6.91(1H, d, J=2.2),                                              7.05˜7.28(3H, m), 7.31˜7.42                                       (2H, m), 7.59(1H, dd, J=8.0, 1.9),                                            7.90˜8.00(2H, m), 8.12(1H, br.s)                                Intermed.                                                                             (CDCl3): 0.52˜0.61(6H, m), 0.89                                 108     (9H, m), 2.79(1H, dd, J=12.1,                                                 4.4), 2.89(1H, dd, J=12.1, 7.7),                                              2.96(3H, s), 3.04(2H, m), 4.15                                                (2H, m), 4.84(1H, m), 6.82(1H,                                                dd, J=8.5, 2.2), 6.92(1H, d,                                                  J=1.9), 7.17(1H, dd, J=8.8,                                                   1.9), 7.21(1H, dd, J=8.2, 1.4),                                               7.30˜7.42(3H, m), 7.67(1H, d,                                           J=2.2), 7.90˜7.99(2H, m),                                               8.14(1H, br.s)                                                        Intermed.                                                                             (CDCl3): 2.49(3H, d, J=5.2), 3.28                                     112     (1H, d, J=3.0), 3.47(1H, dd,                                                  J=10.7, 8.0), 3.56(1H, dd, J=10.7,                                            4.1), 4.83(1H, q, J=5.5), 4.88(1H, m),                                        5.22(2H, s), 7.09(1H, d, J=8.8), 7.30˜                                  7.48(5H, m), 7.55(1H, dd, J=8.8, 2.5),                                        7.88(1H, d, J=2.2)                                                    Intermed.                                                                             (CDCl3): 0.47˜0.66(6H, m),                                      113     0.85˜0.95(9H, m), 2.52(3H, d, J=5.5),                                   3.28˜3.35(2H, m), 4.66(1H,                                              m), 4.77(1H, m), 5.23(2H, s),                                                 7.09(1H, d, J=8.5), 7.34˜7.52                                           (5H, m), 7.55(1H, dd, J=8.5, 2.5),                                            7.91(1H, d, J=2.2)                                                    Intermed.                                                                             (CDCl3): 0.48˜0.58(6H, m), 0.87                                 114     (9H, m), 2.50(3H, d, J=5.5),                                                  2.80(1H, dd, J=11.8, 4.4), 2.91                                               (1H, dd, J=11.8, 7.4), 4.07(2H,                                               m), 4.69(1H, q, J=5.5), 4.86(1H,                                              dd, J=7.4, 4.4), 5.15(2H, s),                                                 6.77*(1H, d, J=1.9), 6.82(1H,                                                 dd, J=6.3, 2.2), 7.01(1H, d,                                                  J=8.5), 7.20(1H, m), 7.30˜7.48                                          (7H, m), 7.52(1H, dd, J=8.5, 2.2),                                            7.89˜8.00(2H, m), 8.19(1H, s)                                   Intermed.                                                                             (CDCl3): 2.34(3H, s), 2.64(3H,                                        116     s), 8.21(1H, dd, J=9.1, 2.2),                                                 8.81(1H, d, J=2.2), 8.95(1H, d, J=9.1)                                Intermed.                                                                             (CDCl3): 2.25(3H, s), 2.56(3H,                                        117     s), 7.44(2H, m), 7.50(1H, m)                                          Intermed.                                                                             (CDCl3): 2.26(3H, s), 2.60(3H,                                        118     s), 3.05(3H, s), 6.79(1H, s),                                                 7.90(2H, m), 8.24(1H, dd, J=8.1,                                              2.5), 8.55(2H, br.s)                                                  Intermed.                                                                             (CDCl3): 2.27(3H, s), 3.08(3H,                                        119     s), 4.41(2H, s), 6.73(1H, br.s),                                              7.87˜8.09(2H, s), 8.31(1H, dd,                                          J=8.8), 8.58(1H, d, J=10.2)                                           Intermed.                                                                             (DMSO-d6; HCl): 2.10(3H, s), 2.94                                                                      497                                          120     (3H, s), 3.15(2H, d, J=8.2),                                                                           (MH+)                                                3.48(2H, m), 4.39(2H, m), 5.01                                                (1H, m), 6.26*1H, m), 6.84(1H, d,                                             J=8.5), 7.03(1H, s), 7.12(1H,                                                 dd, J=7.1, 6.9), 7.24˜7.33                                              (2H, m), 7.44(2H, d, J=8.5), 7.56                                             (1H, m), 8.01(2H, d, J=6.9),                                                  8.8˜9.1(2H, m), 9.62(1H, m), 11.18                                      (1H, s)                                                               Example (DMSO-d6; 2HCl): 3.02(3H, s),                                                                          455                                          82      3.2˜3.5(4H, m), 4.26(2H, m),                                                                     (MH+)                                                4.84(1H, d, J=9.3), 6.8˜7.5(8H,                                         m), 7.64(1H, s), 7.87(1H, d, J=7.7),                                          8.01(1H, d, J=8.2), 9.0˜9.6                                             (3H, br.s), 11.3(1H, s)                                               Intermed.                                                                             (CDCl3): 2.61(3H, s), 2.62(3H,                                        121     s), 4.18(2H, s), 5.27(2H, s),                                                 7.15(3H, m), 7.35˜7.44(3H, m),                                          7.47(2H, d, J=8.0), 8.16(1H,                                                  dd, J=8.8, 2.2), 8.57(1H, d, J=2.2)                                   Intermed.                                                                             (CDCl3): 2.62(3H, s), 4.19(2H,                                        122     s), 4.43(2H, s), 5.28(2H, s),                                                 7.12˜7.20(2H, m), 7.18(1H, d,                                           J=8.52), 7.24˜7.50(8H, m),                                              8.20(1H, dd, J=8.5, 2.2), 8.59(1H, d, J=2.2)                          Intermed.                                                                             (CDCl3): 2.59(3H, s), 2.72˜2.82(1H,                                                              636                                          123     m), 3.00˜3.08(1H, m), 3.10(2H, m),                                                               (MH+)                                                4.13˜4.20(4H, m), 4.72˜4.77(1H, m), 5.16(2H,                      s), 6.84(1H, dd, J=8.2, 2.2), 6.91(1H,                                        d, J=2.2), 7.05(1H, d, J=8.5),                                                7.13˜7.49(13H, m), 7.57(1H,                                             d, J=8.2), 7.93(1H, d, J=8.5),                                                7.97(1H, d, J=7.7), 8.01(1H, d, J=1.7)                                Example (DMSO-d6; HCl): 2.64(3H, s),                                                                           546                                          83      3.14(2H, m), 3.48(2H, m), 4.31(2H,                                                                     (MH+)                                                s), 4.39(2H, m), 5.00(1H, m), 6.23(1H,                                        br.s), 6.83(1H, dd, J=8.8, 2.2),                                              7.02(1H, d, J=1.9), 7.08˜7.15(3H,                                       m), 7.26˜7.40(6H, m), 7.43(1H, d,                                       J=8.5), 7.51(1H, dd, J=8.8, 1.9),                                             7.80(1H, d, J=1.9), 7.99(1H, d, J=8.8),                                       8.80˜9.10(2H, br), 10.96(1H, s),                                        11.18(1H, s)                                                          Intermed.                                                                             (CDCl3): 1.39(3H, t, J=7.1),                                          124     1.66(3H, s), 3.76(2H, m), 4.05(2H,                                            m), 4.38(2H, q, J=7.1), 7.56(2H,                                              d, J=8.5), 8.03(2H, d, J=8.5)                                         Intermed.                                                                             (CDCl3): 2.61(3H, s), 4.79(2H,                                        125     s), 7.46(2H, d, J=8.0), 7.96(2H,                                              d, J=8.2)                                                             Intermed.                                                                             (CDCl3): 2.14(3H, s), 2.61(3H,                                        126     s), 5.17(2H, s), 7.45(2H, d,                                                  J=8.5), 7.96(2H, d, J=8.5)                                            Intermed.                                                                             (CDCl3): 2.20(3H, s), 2.68(3H,                                        127     s), 5.57(2H, s), 7.73(1H, d, J=8.2),                                          8.22(1H, dd, J=8.2, 1.6),                                                     8.65(1H, d, J=1.6)                                                    Intermed.                                                                             (CDCl3): 2.10(3H, s), 2.56(3H,                                        128     s), 4.18(2H, br.s), 5.12(2H,                                                  s), 7.27˜7.31(3H, m)                                            Intermed.                                                                             (CDCl3): 2.11(3H, s), 2.62(3H,                                        129     s), 3.12(3H, s), 5.18(2H, s),                                                 7.52(1H, d, J=8.0), 7.74(1H, br.s),                                           7.79(1H, dd, J=8.0, 1.6),                                                     8.08(1H, d, J=1.6)                                                    Intermed.                                                                             (CDCl3): 2.12(3H, s), 3.14(3H,                                        130     s), 4.43(2H, s), 5.18(2H, s),                                                 7.55(1H, d, J=8.0), 7.80(1H, bs),                                             7.83(1H, dd, J=8.0, 1.7), 8.12                                                (1H, d, J=1.7)                                                        Intermed.                                                                             (DMSO-d6): 2.05(3H, s), 2.96(3H,                                                                       500                                          131     s), 2.92˜3.00(2H, m), 3.28˜3.32                                                            (MH+)                                                (2H, m), 4.08˜4.13(2H, m), 4.67(1H,                                     br.s), 5.15(2H, s), 5.44(1H, m), 6.76                                         (1H, dd, J=8.2, 1.9), 6.96(1H,                                                d, J=1.9), 7.07˜7.13(1H,                                                m), 7.24˜7.44(4H, m), 7.93˜8.00(3H, m)                    Example (DMSO-d6; HCl): 3.02(3H, s),                                                                           470                                          84      3.25˜3.35(2H, m), 3.43˜3.53(2H, m),                                                        (MH+)                                                4.36˜4.43(2H, m), 4.62(2H, s),                                          5.03(1H, d, J=9.1), 6.26(1H, bs),                                             6.84(1H, dd, J=8.5, 2.2), 7.03(1H, d,                                         J=1.9), 7.12(1H, dd, J=7.1), 7.24˜                                      7.35(2H, m), 7.38(1H, s), 7.44(1H, d,                                         J=3 8.0), 7.47(1H, d, J=8.0), 8.01(1H,                                        d, J=8.2), 9.96(1H, s), 8.90˜9.25(2H,                                   br), 11.21(1H, s)                                                     Intermed.                                                                             (CDCl3): 2.61(3H, s), 3.06(3H,                                        132     s), 7.66(1H, dd, J=8.5, 2.2),                                                 7.71(1H, d, J=8.5), 8.20(1H, d, J=2.2)                                Intermed.                                                                             (CDCl3): 3.09(3H, s), 4.42(2H,                                        133     s), 7.68(1H, dd, J=8.4, 1.8),                                                 7.75(1H, d, J=8.4), 8.21(1H, d, J=1.8)                                Example (DMSO-d6; HCl): 3.07(3H, s),                                                                           520                                          85      2.98˜3.16(2H, m), 3.43˜3.55(2H,                                                            (M +                                                 m), 4.35˜4.44(2H, m), 5.0˜5.08                                                             2)+                                                  (1H, m), 6.38(1H, br.s), 6.84(1H, dd,                                         J=8.5, 2.2), 7.03(1H, d, J=2.2),                                              7.12(1H, dd, J=8.0, 8.0), 7.24(1H,                                            dd, J=8.0, 1.9), 7.30(1H, dd, J=8.0,                                          8.0), 7.44(1H, d, J=8.0), 7.52(1H, d,                                         J=1.9), 7.72(1H, d, J=8.0), 8.00(2H,                                          d, J=8.5), 8.95˜9.08(1H, m), 9.10˜                                9.25(1H, m), 9.47(1H, s), 11.20(1H, s)                                Intermed.                                                                             (CDCl3): 2.64(3H, s), 7.80(1H, dd,                                    134     J=8.2, 2.2), 8.19(1H, d, J=8.2),                                              8.36(1H, d, J=2.2)                                                    Intermed.                                                                             (CDCl3): 2.54(3H, s), 4.25(2H,                                        135     br.s), 7.01(1H, dd, J=8.2, 1.9),                                              7.29(1H, d, J=1.9), 7.74(1H, d,                                               J=8.2)                                                                Intermed.                                                                             (CDCl3): 2.60(3H, s), 3.06(3H, s),                                    136     7.51(1H, dd, J=8.2, 1.9),                                                     7.96(1H, d, J=8.2), 8.16(1H, d, J=1.9)                                Intermed.                                                                             (CDCl3): 3.09(3H, s), 4.41(2H,                                        137     s), 6.76(1H, br.s), 7.53(1H, dd,                                              J=8.2, 2.2), 8.00(1H, d, J=8.2),                                              8.18(1H, d, J=2.2)                                                    Example (DMSO-d6; HCl): 3.08(3H, s),                                                                           566                                          86      3.0˜3.1(2H, m), 3.45˜3.54(2H,                                                              (MH+)                                                m), 4.38˜4.47(2H, m), 4.98˜5.08                                   (1H, m), 6.37(1H, br.s), 6.84(1H, dd,                                         J=8.5, 2.2), 7.03(1H, d, J=2.2),                                              7.06˜7.16(2H, m), 7.30(1H, dd, J=8.2,                                   8.2), 7.44(1H, d, J=8.2), 7.46(1H, d,                                         J=2.2), 7.94(1H, d, J=8.2), 8.01(2H, d,                                       J=8.5), 8.94˜9.06(1H, br), 9.10˜9.24(1H,                          br), 9.36(1H, s), 11.21(1H, s)                                        Intermed.                                                                             (CDCl3): 2.55(3H, s), 2.70(3H,                                        138     s), 4.31(2H, s), 5.17(2H, s),                                                 6.95(1H, s), 7.02(1H, d, J=8.5),                                              7.15˜7.21(2H, m), 7.23˜7.31(2H,                                   m), 7.33˜7.44(6H, m), 7.74(1H, dd,                                      J=8.5, 2.2), 8.14(1H, d, J=2.8)                                       Intermed.                                                                             (CDCl3): 2.72(3H, s), 4.33(2H,                                        139     s), 4.37(2H, s), 5.18(2H, s),                                                 6.98(1H, s), 7.04(1H, d, J=8.5),                                              7.16˜7.22(2H, m), 7.25˜7.32(2H,                                   m), 7.34˜7.43(6H, m), 7.77                                              (1H, dd, J=8.8, 1.9), 8.14(1H, d,                                             J=2.2)                                                                Intermed.                                                                             (DMSO-d6): 2.51(3H, s), 2.69(2H,                                                                       651                                          140     m), 2.94(2H, m), 4.07(2H, m),                                                                          (MH+                                                 4.11(2H, s), 4.60(1H, m), 5.15(2H,                                            s), 6.74(1H, d, J=10.7), 6.94                                                 (1H, m), 7.03˜7.48(16H, m),                                             7.91˜8.00(3H, m), 11.08(1H, s)                                  Example (DMSO-d6; HCl): 2.57(3H, s),                                                                           561                                          87      3.00˜3.30(2H, m), 3.47(2H, m),                                                                   (MH+)                                                4.18(2H, s), 4.37(2H, m), 4.92                                                (1H, d, J=9.6), 6.14(1H, br.s),                                               6.82(1H, dd, J=8.5, 2.2), 6.91                                                (1H, d, J=8.2), 7.02˜7.12(3H, m),                                       7.18˜7.21(2H, m), 7.25˜7.35(4H, m),                               7.41(1H, d, J=2.2)7.43(1H, d,                                                 J=8.0), 7.97˜8.02(2H, m)                                        Intermed.                                                                             (CDCl3): 1.09(6H, t, J=7.1),                                          141     2.55(3H, s), 3.30(4H, q, J=7.1),                                              5.17(2H, s), 6.91(1H, bs), 6.99(1H,                                           d, J=8.5), 7.36˜7.44(5H, m),                                            7.69(1H, dd, J=8.5, 2.2), 8.02                                                (1H, d, J=2.2)                                                        Intermed.                                                                             (CDCl3): 1.10(6H, t, J=7.4),                                          142     3.31(4H, q, J=7.4), 4.39(2H, s),                                              5.19(2H, s), 6.94(1H, bs), 7.02(1H,                                           d, J=8.8), 7.36˜7.44(5H, m),                                            7.72(1H, dd, J=8.8), 8.03(1H,                                                 d, J=2.2)                                                             Intermed.                                                                             (DMSO-d6): 0.88(6H, t, J=7.1),                                                                         603                                          143     2.68(2H, d, J=5.8), 2.95(2H,                                                                           (MH+)                                                m), 3.07(4H, q, J=7.1), 4.09(2H, m),                                          4.58(1H, m), 5.13(2H, s), 6.76(1H,                                            d, J=6.6), 6.92˜7.14(4H, m),                                            7.24˜7.44(7H, m), 7.54(2H, d, J=6.9),                                   7.90˜8.02)2H, m)                                                Example (DMSO-d6; HCl): 0.95(6H, t, J=7.1),                                                                    513                                          88      3.13(4H, q, J=7.1), 2.95˜3.25                                                                    (MH+)                                                (2H, m), 3.48(2H, m), 4.37(2H, m),                                            4.88(1H, d, J=10.2), 6.11(1H,                                                 br.s), 6.80˜6.88(2H, m), 6.95˜                                    7.04(2H, m), 7.12(1H, dd, J=8.0,                                              0.8), 7.27˜7.34(2H, m), 7.44(1H, d,                                     J=8.0), 8.01(2H, d, J=8.5),                                                   8.54(1H, s), 8.6˜9.1(2H, br),                                           9.85(1H, s), 11.19(1H, s)                                             Intermed.                                                                             (CDCl3): 2.75(6H, s), 4.41(2H, s),                                    144     5.29(2H, s), 7.15(1H, d, J=8.8),                                              7.35˜7.45(3H, m), 7.47˜7.52(2H,                                   m), 8.17(1H, dd, J=8.8, 2.2), 8.54(1H, d, J=2.2)                      Intermed.                                                                             (CDCl3): 0.52˜0.62(6H, m),                                      145     0.85˜0.94(9H, m), 2.71(6H, s),                                          3.26˜3.35(2H, m), 4.76(1H, t,                                           J=6.2), 5.19(2H, s), 7.05(1H, d,                                              J=8.5), 7.32˜7.44(3H, m),                                               7.46˜7.55(3H, m), 7.90(1H, d, J=2.2)                            Intermed.                                                                             (CDCl3): 0.48˜0.58(6H, m),                                      146     0.87(9H, t, J=7.8), 2.71(6H, s),                                              2.74˜2.82(1H, m), 2.85˜2.91(1H,                                   m), 3.04(2H, m), 4.13(2H, m),                                                 4.8˜4.86(1H, m), 5.16(2H, s),                                           6.82(1H, dd, J=8.5, 2.2), 6.88                                                (1H, d, J=2.2), 7.01(1H, d, J=8.5),                                           7.20(1H, m), 7.29˜7.42(6H, m),                                          7.45˜7.52(2H, m), 7.91(1H,                                              d, J=8.5), 7.96˜7.98(2H, m),                                            8.20(1H, br.s)                                                        Intermed.                                                                             (DMSO-d6): 2.62(2H, m),  560                                          147     2.71˜2.75(2H, m), 2.95(2H, m), 4.08                                                              (MH+)                                                (2H, m), 4.65˜4.72(1H, m), 5.24                                         (2H, s), 5.46(1H, br.s), 6.75(1H,                                             dd, J=8.5, 2.2), 6.95(1H,                                                     d, J=2.2), 7.10(1H, dd, J=7.7,                                                7.7), 7.24˜7.44(6H, m), 7.48˜7.54                                 (2H, m), 7.57(1H, dd, J=8.5, 2.2),                                            7.78(1H, d, J=2.2), 7.95(1H,                                                  d, J=8.5), 7.98(1H, d, J=8.2),                                                11.10(1H, s)                                                          Example (DMSO-d6; HCl): 2.71(6H, s),                                                                           470                                          89      2.76˜2.82(2H, m), 3.02(2H, m),                                                                   (MH+)                                                4.13(2H, m), 4.64˜4.70(1H, m),                                          6.76(1H, dd, J=8.5, 2.2), 6.96                                                (1H, d, J=2.2), 7.01(1H, d, J=8.2),                                           7.10(1H, dd, J=8.0, 8.0), 7.28                                                (1H, dd, J=8.0, 8.0), 7.38˜7.45                                         (2H, m), 7.65(1H, d, J=2.2), 7.96                                             (1H, d, J=8.5), 7.98(1H, d, J=8.0),                                           8.28(1H, br.s), 11.15(1H, s)                                          Intermed.                                                                             (CDCl3): 2.70(1H, d, J=8.5),                                                                           560                                          148     2.81(1H, d, J=8.5), 2.90(3H, s),                                                                       (MH+)                                                3.04(2H, m), 3.25(3H, s), 4.12(2H, t,                                         J=4.7), 4.32(1H, dd, J=8.5, 4.7),                                             5.07(2H, s), 6.82(1H, dd, J=8.5,                                              2.2), 6.88(1H, s), 6.96(1H, d,                                                J=8.2), 7.09(1H, dd, J=8.5, 1.7),                                             7.19(1H, dd, J=8.8, 1.4), 7.29˜7.45                                     (7H, m), 7.51(1H, d, J=1.9), 7.90(1H, d,                                      J=8.5), 7.96(1H, d, J=7.7),                                                   8.29(1H, m)                                                           Example (DMSO-d6; HCl): 2.96(3H, s),                                                                           470                                          90      3.19(3H, s), 3.23(2H, d, J=6.6),                                                                       (MH+)                                                3.46(2H, m), 4.37(2H, m), 4.54(1H,                                            t, J=6.6), 6.84(1H, dd, J=8.5,                                                1.9), 6.96(1H, d, J=8.5), 7.01˜7.08                                     (2H, m), 7.12(1H, dd, J=7.4, 7.4),                                            7.23(1H, m), 7.30(1H, m), 7.44(1H, d,                                         J=8.0), 8.01(2H, d, J=8.2), 8.85(1H, s),                                      8.96(1H, br.s), 10.15(1H, s), 11.19(1H, s)                            Example (DMSO-d6; HCl): 2.96(3H, s,                                                                            487                                          91      3.18(3H, s), 3.18(1H, m), 3.31(1H,                                                                     (MH+)                                                m), 3.40(2H, m), 4.38(2H, m),                                                 4.48(1H, m), 6.95(1H, d, J=8.0),                                              7.05(1H, m), 7.16(1H, dd, J=8.5,                                              2.2), 7.22(1H, d, J=2.2), 7.46                                                (2H, m), 7.68(1H, d, J=2.2),                                                  7.98(1H, m), 8.27(2H, m), 8.82                                                (1H, br.s), 10.12(1H, br.s)                                           Example (DMSO-d6; 2HCl): 2.94(3H. s),                                                                          469                                          92      3.17(3H, s), 3.22(2H, m), 3.46                                                                         (MH+)                                                (2H, m), 4.38(2H, m), 4.51(1H, m),                                            6.81˜6.90(2H, m), 7.03(2H, dd,                                          J=6.3, 2.2), 7.12(2H, dd, J=7.4,                                              7.4), 7.27˜7.33(1H, m), 7.44(1H, d,                                     J=8.0), 8.01(2H, d, J=8.5),                                                   8.8˜9.2(3H, br), 11.20(1H, s)                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Compound     *Intrinsic activity (%)                                                                     ED.sub.50 (nM)                                     ______________________________________                                        Iosproterenol                                                                              100           140                                                BRL37344     29            104                                                CL316, 243   9             1700                                               Example 1    80            340                                                Example 2    120           0.18                                               Example 4    80            0.52                                               Example 5    114           66                                                 Example 6    119           33                                                 Example 7    95            18                                                 Example 8    47            720                                                Example 9    85            750                                                Example 10   47            150                                                Example 11   95            26                                                 Example 12   113           0.14                                               Example 13   110           2.7                                                Example 14   97            2.8                                                Example 15   88            110                                                Example 16   99            30                                                 Example 17   53            910                                                Example 18   90            32                                                 Example 25   95            2.1                                                Example 28   97            1000                                               Example 29   120           250                                                Example 30   110           1700                                               Example 31   100           2200                                               Example 32   98            1600                                               Example 34   37            4600                                               Example 35   90            520                                                Example 38   76            0.006                                              Example 40   97            200                                                Example 41   63            600                                                Example 43   104           85                                                 Example 45   89            17                                                 Example 47   86            2000                                               Example 48   73            220                                                Example 50   85            0.94                                               Example 52   78            2.6                                                Example 54   109           8.4                                                Example 55   76            230                                                Example 56   97            630                                                Example 57   68            230                                                Example 58   91            550                                                Example 62   106           210                                                Example 66   106           72                                                 Example 67   109           28                                                 Example 68   92            38                                                 Example 69   94            0.016                                              Example 70   76            300                                                Example 71   97            180                                                Example 72   80            0.00003                                            Example 73   102           0.038                                              Example 74   114           0.74                                               Example 75   105           88                                                 Example 76   131           520                                                Example 77   100           21                                                 Example 78   110           51                                                 Example 79   107           1.2                                                Example 80   110           57                                                 Example 81   98            6.2                                                Example 82   130           2800                                               Example 83   79            740                                                Example 84   71            58                                                 Example 85   70            56                                                 Example 87   138           84                                                 Example 88   86            390                                                Example 89   73            350                                                Example 90   102           190                                                Example 92   81            280                                                ______________________________________                                         *Relative activity for isoproterenol                                     

                  TABLE 3                                                         ______________________________________                                        Compound     *Intrinsic activity (%)                                                                     ED.sub.50 (nM)                                     ______________________________________                                        Isoproterenol                                                                              100           1.7                                                Example 2    82            56                                                 Example 4    88            0.7                                                Example 7    90            1200                                               Example 9    106           250                                                Example 25   70            510                                                Example 31   103           7700                                               Example 32   94            290                                                Example 38   103           2.6                                                Example 40   92            13                                                 Example 41   109           240                                                Example 43   77            4                                                  Example 50   112           0.19                                               Example 52   100           0.38                                               Example 54   118           25                                                 Example 67   94            54                                                 Example 69   107           0.65                                               Example 71   88            110                                                Example 72   96            0.54                                               Example 92   126           1900                                               ______________________________________                                         *Relative activity for isoproterenol                                     

What is claimed is:
 1. A compound represented by the general formula (I) or a salt thereof: ##STR27## in which R represents hydrogen atom or methyl, R¹ stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R² stands for hydrogen atom, hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ being lower alkyl, benzyl or NR⁴ R^(4') and R^(6') being hydrogen atom or lower alkyl, and R⁴ and R^(4') may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R⁶ represents hydrogen atom or lower alkyl, X is secondary nitrogen atom, R⁹ stands for hydrogen atom and either one of R⁷ and R⁸ is hydrogen atom and the other one is hydrogen atom, amino, acetyl amino or hydroxy, and *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl.
 2. A compound represented by the general formula (I) or a salt thereof as claimed in claim 1: ##STR28## in which R represents hydrogen atom, R¹ stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R² stands for hydrogen atom, hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ being lower alkyl, benzyl or NR⁴ R^(4') and R^(6') being hydrogen atom or lower alkyl, and R⁴ and R^(4') may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R⁶ represents hydrogen atom or lower alkyl, X is secondary nitrogen atom, R⁹ stands for hydrogen atom and either one of R⁷ and R⁸ is hydrogen atom and the other one is hydrogen atom, amino, acetylamino or hydroxy, and *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl.
 3. A compound represented by the general formula (I) or a salt thereof as claimed in claim 2: ##STR29## in which R represents hydrogen atom, R¹ stands for hydrogen atom, fluorine atom, chlorine atom, hydroxy or benzyloxy, R² stands for hydrogen atom, hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6') and either one of R⁴ and R^(4') is hydrogen atom and the other one is hydrogen atom, lower alkyl or benzyl, with R⁵ being lower alkyl, benzyl or dimethylamino and R^(6') being hydrogen atom or lower alkyl, R⁶ represents hydrogen atom or lower alkyl, X is secondary nitrogen atom, R⁹ stands for hydrogen atom and either one of R⁷ and R⁸ is hydrogen atom and the other one is hydrogen atom, amino, acetylamino or hydroxy, and *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl.
 4. A compound represented by the general formula (I) or a salt thereof as claimed in claim 2: ##STR30## in which R represents hydrogen atom, R¹ stands for hydrogen atom, halogen atom, hydroxy or benzyloxy, R² stands for hydroxymethyl, NHR³, SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6') and R⁴ and R^(4') may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, with R⁵ being lower alkyl, benzyl or NR⁴ R^(4') and R^(6') being hydrogen atom or lower alkyl, R⁶ represents hydrogen atom or lower alkyl, X is secondary nitrogen atom, R⁹ stands for hydrogen atom and either one of R⁷ and R⁸ is hydrogen atom and the other one is hydrogen atom, amino, acetylamino or hydroxy, and *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl.
 5. A compound or a salt thereof as claimed in claim 2, wherein, in the general formula (I), both R and R¹ represent hydrogen atom, R² stands for hydroxymethyl, NHR³ or SO₂ NR⁴ R^(4'), wherein R³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6') and R⁴ and R^(4') may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, with R⁵ being lower alkyl, benzyl or NR⁴ R^(4').
 6. A compound or a salt thereof as claimed in claim 2, wherein, in the general formula (I), R denotes hydrogen atom, R¹ stands for halogen atom or hydroxy, R² stands for NHSO₂ R⁵ or SO₂ NR⁴ R^(4'), wherein R⁵ is lower alkyl, benzyl or NR⁴ R^(4') and R⁴ and R^(4') may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl.
 7. A compound represented by the general formula (I) or a salt thereof as claimed in claim 2: ##STR31## wherein R represents hydrogen atom, R¹ stands for hydrogen atom, halogen atom or hydroxy, R² stands for hydrogen atom, R⁶ represents hydrogen atom or lower alkyl, X is secondary nitrogen atom, R⁹ stands for hydrogen atom and either one of R⁷ and R⁸ is hydrogen atom and the other one is hydrogen atom, amino, acetylamino or hydroxy, and *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl.
 8. A compound represented by the general formula (I) or a salt thereof as claimed in claim 1: ##STR32## wherein R represents methyl, R¹ stands for hydrogen atom, halogen atom, hydroxy, amino or hydroxymethyl, R² stands for NHR³ or SO₂ NR⁴ R^(4'), wherein R³ represents SO₂ R⁵, with R⁵ being lower alkyl, benzyl or NR⁴ R^(4'), and R⁴ and R^(4') may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R⁶ represents hydrogen atom or lower alkyl, X is secondary nitrogen atom, R⁹ stands for hydrogen atom and either one of R⁷ and R⁸ is hydrogen atom and the other one is hydrogen atom, amino, acetylamino or hydroxy, and *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl.
 9. A compound represented by the general formula (III) ##STR33## in which Y represents hydrogen atom or a protecting group for the amino group, R⁶ is hydrogen atom or lower alkyl, X is secondary nitrogen atom, R^(9') is hydrogen atom and either one of R^(7') and R^(8') is hydrogen atom and the other one is hydrogen atom, acetylamino or a protected hydroxyl group protected by a protecting group A", and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl.
 10. A compound represented by the general formula (IV) ##STR34## in which R^(1') represents hydrogen atom, halogen atom, a protected hydroxyl group protected by a protecting group A, a protected amino group protected by acetyl group or a protected hydroxymethyl group in which the hydroxyl group is protected by acetyl group, R⁶ stands for hydrogen atom or lower alkyl, Y' is hydrogen atom or a protecting group for the amino group, X is secondary nitrogen atom, R^(9') is hydrogen atom and either one of R^(7') and R^(8') is hydrogen atom and the other one is acetylamino R^(7') and R^(8') is hydrogen atom and the other one is acetylamino or a protected hydroxyl group protected by a protecting group A", A' represents a protecting group for the hydroxyl group, *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl.
 11. A compound or a salt thereof as claimed in claim 2, wherein the compound is selected from the group consisting of (R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; (S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N-[5-[2-[2-(3-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N-[5-[2-[2-(3-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N-[5-[2-[2-(6-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N-[5-[2-[2-(6-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; (R)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide; (S)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide; N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide; N-methyl-3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]benzenesulfonamide; N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]methanesulfonamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl-2-hydroxyphenyl]formamide; N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]formamide; N-[3-[2-[[1-(9H carbazol-2-yloxy)propan-2R-yl]amino]-1-hydroxyethyl]phenyl]methanesulfonamide; 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxy-3-nitrophenyl)ethanol; 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-amino-4-hydroxyphenyl)ethanol; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]urea, N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]urea; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]formamide; N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N,N-dimethylsulfamide; N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide; 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-(benzyloxy)phenyl]ethanol and 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-hydroxyphenyl]ethanol; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-2-propanesulfonamide; 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-nitrophenyl)ethanol; N'-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]-N,N-dimethylsulfamide; 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-aminophenyl)ethanol; 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(hydroxymethyl)-4-hydroxyphenyl]ethanol; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-3-hydroxyphenyl]methanesulfonamide; N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamide; (R)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide; (S)-N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide; N-[3-[2-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide; N-[5-[2-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; (R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide; (S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide; (R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide; (S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide; N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-iodophenyl]methanesulfonamide; N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]-N,N-dimethylsulfamide; N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]-N,N-dimethylsulfamide; (R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide; (R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenyl]methanesulfonamide; N'-(5-[2-[2-(9H-carbazol-2-yloxy)ethylamino-1-hydroxyethyl]-2-aminophenyl]-N-benzyl-N-methylsulfamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]methanesulfonamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxymethylphenyl]methanesulfonamide; N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide; N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N-benzyl-N-methylsulfamide and N'-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-diethylsulfamide.
 12. A compound or a salt thereof as claimed in claim 8, wherein the compound is selected from the group consisting of 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxyphenyl)ethanol, 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-fluorophenyl)ethanol, 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-hydroxyphenyl)ethanol, (R,R)-2-[N-[1-(9H-carbazol-2-yloxy)propan-2-yl]amino]-1-phenylethanol, 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanol, (R)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanol, (S)-[2-[N-2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanol, 2-[N-[2-(3-acetylamino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanol, 2-[N-[2-(3-amino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanol, 2-[N-[2-(3-hydroxy-9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanol, 2-[N-[2-(6-amino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanol, 2-[N-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanol, and 2-[N-[1-(9H-carbazol-2-yloxy)propan-2-yl]amino]-1-phenylethanol.
 13. A compound or a salt thereof as claimed in claim 10, wherein the compound is selected from the group consisting of N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamide, N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-aminophenyl]methanesulfonamide and N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-chlorophenyl]methanesulfonamide.
 14. A pharmaceutical composition comprising as an effective component, a compound or a salt thereof as claimed in claim 1, in a physiologically or pharmacologically acceptable carrier.
 15. A pharmaceutical composition as claimed in claim 14, in the form of a drug suitable for therapeutic treatment or preventive treatment of one of diabetes, obesity and hyperlipemia.
 16. A method for producing a compound represented by the general formula (I) ##STR35## in which R represents hydrogen atom, R¹ stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxy-SO₂ NR⁴ R^(4') or nitro, wherein R³ is hydrogen atom, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ being lower alkyl, benzyl or NR⁴ R^(4') and R^(6') being hydrogen atom or lower alkyl, and R⁴ and R^(4') may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R⁶ represents hydrogen atom or lower alkyl, X is secondary nitrogen atom, R⁹ stands for hydrogen atom and either one of R⁷ and R⁸ is hydrogen atom and the other one is hydrogen atom, amino, acetylamino or hydroxy, and *1 indicates an asymmetric carbon atom and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl, comprising the step of reacting a compound represented by the general formula (II) ##STR36## in which R^(1') represents hydrogen atom, halogen atom, a protected hydroxyl group protected by a protecting group A, a protected amino group protected by acetyl group or a protected hydroxymethyl group protected by acetyl group, R^(2') stands for hydrogen atom, for a protected hydroxymethyl group in which the hydroxyl group is protected by a protecting group A"', for NHR^(3'), for SO₂ NR⁴ R^(4') or for nitro, wherein R^(3') represents a protecting group for the amino group, methyl, SO₂ R⁵, formyl or CONHR^(6'), with R⁵ being lower alkyl, benzyl or NR⁴ R^(4') and R^(6') being hydrogen atom or lower alkyl, R⁴ and R^(4') may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R⁶ denotes hydrogen atom or lower alkyl, A' represents a protecting group for the hydroxyl group, B is bromine atom or iodine atom and *1 indicates an asymmetric carbon atom is reacted with a compound represented by the general formula (III) ##STR37## in which Y represents hydrogen atom, R⁶ is hydrogen atom or lower alkyl, X is secondary nitrogen atom, R^(9') is hydrogen atom and either one of R^(7') and R^(8') is hydrogen atom and the other one is hydrogen atom, acetylamino or a protected hydroxyl group protected by a protecting group A", and *2 indicates that the carbon atom is asymmetric provided that R⁶ is lower alkyl,wherein the protecting groups A, A', A", and A"' as well as the protecting group for the amino group in R^(3') and the protecting acetyl group in R^(1') are eliminated for protection with the proviso that the protecting group A is not eliminated if A is benzyl and R¹ is benzyloxy. 